Re: Telomeres, mutation rates and "breakthroughs"

From: phil osborn (
Date: Sat May 06 2000 - 23:44:24 MDT

>From: "Robert J. Bradbury" <>
>Subject: Telomeres, mutation rates and "breakthroughs"
>Date: Mon, 1 May 2000 06:41:54 -0700 (PDT)>
>On Mon, 1 May 2000, John Clark wrote:
> > > I had commented on the problem that increased numbers of cell
> > > would effectively lead to greater malignancy.
> >
>To which John had replied:
> > But after 93 divisions, 50% more than in a normal lifetime, there was
> > no evidence of an increase in malignancy. Ok the divisions were done in
> > vitro not in an animal but I would think, perhaps foolishly, that if
> > anything that would increase the likelihood of cancer occurring in the
> > cells not decrease it.
>John, has pointed out the points in my argument that I'm glossing over.
>The question is: What are the sources of mutation that lead to malignancy
>(and perhaps aspects of aging)?
>(a) Radiation
>(b) Oxidative stress
>(c) Toxins in the cellular "environment" (derived from food).
>(d) Mutations by DNA Polymerase in copying the DNA.
>Now, look at the difference between replication in the laboratory dish
>where you are pushing the cells as fast as possible (about 1 generation
>per day) in "perfect" culture media, with much lower exposure to toxins
>a very uniform level of oxygen (so you can tune the antioxidant defenses
>and/or repair rates appropriately) and a much reduced level of radiation
>esposure simply due to a shorter time period.
>It is well known that DNA damage "cleanup" is supposed to occur during
>both transcription and DNA replication. This is however imperfect and
>certain types of damage result in repairs that must cause mutations
>(otherwise *where* would they come from?).

I'm trying to recall the work I saw covered in Scientific American a few
years back relating chaos theory to cell aging.... O'well. Maybe it will
come to me later. Anyway, there are other systemic causes for "mutation"
that are usually not mentioned simply because we don't understand them yet
in a way that easilly lends itself to quantitative experiments.

For example, considering the DNA/RNA machinery as a kind of computer, there
are certain sets of instructions that are considered valid and others that
will be treated as nonsense. However, programmers only have so much time
and energy to devote to finding bugs and hidden weaknesses in code, and
companies must balance that expense against the needs of competition. These
factors can easilly be translated into system constraints that must also
apply to cell DNA/RNA programming.

Thus, the engineering tradeoffs dictate that in a system as complex as a
cell, there WILL be bugs and weaknesses, but that they can't be prevalent or
serious enough that most cells will succumb to them much of the time. Part
of the information that serves as input to the cell is from the surrounding
chemical and probably electrical environment. Cells have the capacity to
alter themselves into variants on the main program as the situation
dictates. Statistically, there is the tiny chance that one of the lethal
variants of the signals will get through.

However, as I'm vaguely recalling from the Sci. Am. article, cells also tend
to go crazy when pushed somehow outside the normal operating parameters.

Koestler wrote about the DNA code being taped over - as with a piano with
certain keys taped over - such that only certain potentialities are
expressed. As cells age, however, they tend to drift back toward a more
general expression - to become less differentiated, as the "tape" comes
loose at random points, until they conclude that somehow they are not
fulfilling their mission - or the demented version of it that now is the
controlling goal.

When cells conclude that they are not fulfilling their mission - or, more
concretely, when signals from the cell surround indicate that it is not
capable of meeting its programmed challenges, what is the response going to
be? ... To divide, obviously. If one cell is not enough, then maybe a
million will do the trick.

This is what cells do normally all the time, dictated by demand. But when
the cell has lost its way and is pursueing some demented purpose based on
mutations or simply the improper access to code that is supposed to be
dormant - like the telomerase gene - then no number of divisions will
suffice to yield a satisfactory return signal. This, we call a tumor. The
tumor will normally succumb when its telomeres shorten to much, but if it
also manages to access the telomerase gene, then the whole system is in

So, what kinds of code correction systems keep these cells in line well
beyond the normal limits, as we have been discussing?

Is it possible that one of the reasons for the apparent extended
youthfulness, etc., exhibited in the recent calve clones or some of the cell
culture experiments is due to the fact that the stable environment, with
only cells of the same kind present, made for a much stronger reinforcement
signal pattern to the cells of each generation? Instead of the chance of
stray signals from surrounding tissue or debris or viruses, etc., confusing
the cell as to its identity and slipping through one of the programming
holes, each newly divided heart muscle cell received the unambiguous
message, "you're a heart muscle cell... you're a heart muscle cell...
you're a heart muscle cell... "

Thus, the normal correction procedures that keep a cell on track might use
that unambiguous signal as a referent, and actually clean up a lot of
accumulated error.
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