Speculation: Origin of apoptosis by ordinary mechanism run amok

• From: anon1@xxxxxxx
• Date: Wed, 1 Feb 2006 09:33:34 -0800

Apoptosis (programmed cell death) involves a cascade which ends with
rapidly cleaving just about every protein in the cell, totally
disrupting all biochemical reactions, terminating the ability of the
cell to perform respiration and other essential functions. But cleaving
proteins is a normal function of a living cell, at a much lower level
of activity in a well regulated way. After polypeptides are built from
amino acids, per sequences of DNA-base triples, and they fold to form
proteins, over time they naturally suffer damage. If they are allowed
to remain indefinitely, eventually they may be damaged enough that they
mal-function, catalyzing new reactions that are harmful to the cell.
Also foreign proteins sometimes leak into the cell, and it's not good
to allow them to stay around and catalyze their own alien reactions.

So evolution has produced cleaving agents which slowly act on all
proteins in the cell, cleaving them back to lone amino acids, to
prevent the build-up of damaged proteins or foreign proteins. Thus the
protein composition of the cell is an equilibrium between production
and degradation via cleaving.

This background mechanism also makes regulation of protein quantity easier
than otherwise. Sometimes the quantity of some protein needs to be
increased, and sometimes it needs to be decreased. If there were no
background process of getting rid of proteins, then there would need
to be two specific mechanisms for regulating the amount of each protein,
one to make it from polypeptides (easy, use DNA triples), and one to
specifically degrade it when no longer desired (very difficult to
imagine any way to evolve such a mechanism, except perhaps by an immune
type of reaction, but that's not easy at all). The easy process of
producing the protein, and the more difficult process of specifically
degrading it, would have to be regulated in reverse sense, one up while
other down, and vice versa. But with cleaving going on all the time,
all the cell needs to do is stop new production of a protein and after
a short time most the old copies of that protein are degraded. So
regulation is easy, regulate production up or down as needed, and just
let background cleaving go at the same speed all the time, and the
balance between the two determines increase or decrease in the specific
protein.

Now the background cleaving process must itself be regulated, not to go
up and down as needed like specific protein production, but just to
keep the background rate "just right" at a low but nonzero level so all
the specific protein-productions have an easy time swinging above or
below that level as needed. But what happens when something goes wrong
with regulation of the background rate of protein cleaving. What if due
to a flaw in the cell's genome, it's unable to function propery under
some particular environmental stress such as a particular toxin,
specifically what if the mechanism for controlling the
background-cleaving process stops working properly, and the level of
the enzyme for cleaving increases to such a high level that most
protein production can't keep up with it. If the cleaving enzyme acts
on itself (after all it is itself a protein), maybe that is not much of
a problem, the enzyme cleaves most of itself until the quantity is
reduced back to a near-normal level. (In fact in some primitive
biochemistries maybe that's how regulation of the protein-cleaving
enzyme works anyway!) But if the protein-cleaving enzyme is resistant
to its own action on itself, then such self-regulation wouldn't occur,
and lack of any other regulation of production of that enzyme would
allow it to increase without bound, i.e. cleaving run amok.

I'm speculating first that such amok-cleaving might actually occur
occasionally under some kinds of stress, such as specific toxins, or
within a cell that has suffered a mutation in whatever mechanism
regulates the production of the protein-cleaving enzyme. In the future,
after Venter's group has done a lot of shotgun sequencing of whole
ecosystems, and thereby learned of many DNA sequences never before
known (because they didn't occur in easily-cultured microbiota), and
then devised probes for the most common of those newly-discovered DNA
sequences to spot (by flourescence for example) those specific cells
containing those sequences, then performed hill-climbing to optimize a
culture for those particular cells, and actually cultured them for the
first time ever, then the next step might be to devise micro-arrays of
protein expression to analyze which genes for which proteins within
these single-celled species are expressed under which circumstances.
One of the surprising (except to me) results of this analysis might be
that amok protein cleaving actually does occur in some currently-living
species during certain specific extreme kinds of stress such as
specific toxins.

Secondly, I speculate that such amok cleaving might actually be a
transitional form between uni-cellular death-under-stress and metazoan
programmed cell death (apoptosis). Perhaps long ago, when the most
primitive metazoans evolved, they didn't have any specific mechanism
for apoptosis, but occasionally a toxin or other stressor might cause
some cells in the embryo to suffer amok cleaving. If the resultant
embryo after those cells died was by chance better fit than the
original, there'd be selection to increase the proportion of animals
with susceptability to that particular toxin or other stressor, and by
mutation there'd be hill-climbing toward those unwanted cells being
more susceptable to that toxin, and by further mutation there'd be
hill-climbing to actually produce that toxin within those cells that
needed to die to enhance the function of the embryo, and eventually
this all would evolve to the kind of apoptosis cascade we see today
where no external toxin or other stressor is needed to kill of groups
of cells no longer needed, such as tissue between fingers, instead now
chemical signals determine which cells need to die, causing those cells
to express whatever trigger chemical is needed to start the apoptosis
cascade, resulting in amok-cleaving totally under control of the
genome.

Am I the first to propose this idea?

Also, yesterday when I proposed the method for using probes for new
DNA sequences and gradient of parameters to optimize conditions for the
corresponding new species of microbiota so that they can be cultured
for the first time ever and then fully sequenced as individual
species/strains and then studied further, followup to:
http://groups.google.com/group/sci.bio.evolution/msg/d8f3c2bcc993546a
= Message-ID: <drlnbg$2eev$1@xxxxxxxxxxxxxxxxxxx>
(my followup hasn't yet appeared in Google Groups, because that
newsgroup is manually moderated, sigh), was I the first to propose that
specific combination of methodology?)

Also, would Venter be interested in any of my ideas for making further
use of the data he's currently collecting, and if so is there anybody
here or in the other newsgroup who has a way to relay my ideas to him?
..

.

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