Re: Speculation: Origin of apoptosis by ordinary mechanism run amok

• From: "Noone Inparticular" <unreve89@xxxxxxxxxxx>
• Date: 1 Feb 2006 09:56:14 -0800

anon1@xxxxxxx wrote:
> 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?

Dunno. It's all very confused. "Amok cleaving" is a weird way of saying
it. I presume you mean "unregulated" cleaving, whatever that might
mean. If so, this is not apoptosis. Further, apoptosis is fairly well
understood and while there are some mechanisms that regulate protein
stability, the principle feature of apoptosis is select cleavage of
*DNA*. In fact, in the early days of studing this process, apoptosis
was often demonstrated by a "laddering" of DNA (due to cleavage of the
molecule at discrete nucleosomal sites).

I really can't see how you go from "amok cleaving" to the transition to
metazoans, but this is probably because your whole thesis is terribly
confused. Others may be able to parse what you are trying to say (I
can't, unfortunately), but based on your (apparently) incomplete
understanding of apoptosis (you're aware that apoptosis is not the only
form of programmed cell death, right?) I suspect there isn't much
there. You might try simplifying your verbiage.

>
> 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?
> .

.

• References:
  • Speculation: Origin of apoptosis by ordinary mechanism run amok
    • From: anon1

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