From: Rafal Smigrodzki (rafal@smigrodzki.org)
Date: Tue Apr 29 2003 - 14:24:25 MDT
Aubrey de Grey wrote:
<snip>
This seems to me to explain why (as far as we
can tell) the code disparity is in fact vastly harder for evolution to
solve than either of the other two hurdles.
### We seem to agree that code disparity was the main problem in
transferring mt genes to the nucleus, although other factors like
hydrophobicity could play a role as well.
------------------------------
> ### You are talking about the so called "fatty streaks", right? Fatty
> streaks can fully disappear.
This is news to me. Can you give references? This certainly flies in
the face of all I've ever come across on fatty streaks.
### See: Desurmont C. Caillaud JM. Emmanuel F. Benoit P. Fruchart JC. Castro
G. Branellec D. Heard JM. Duverger N. Complete atherosclerosis regression
after human ApoE gene transfer in ApoE-deficient/nude mice. [Journal
Article] Arteriosclerosis, Thrombosis & Vascular Biology. 20(2):435-42, 2000
Feb.
I also dimly remember reading some Scientific American articles claiming
reversibility of fatty streaks. I think there were some experiments made on
the Watanabe rabbits some years ago, involving gene therapy, with regression
of lesions.
----------------------------------------
> The only way you can tell there is totally indigestible stuff in the
> plaque is if you cannot digest it in vitro in cell culture
True. As far as I'm aware, no one has done the simple experiment of
exposing macrophages to atheroma in culture and seeing what happens.
Or more likely, it was done 50 years ago and the result was boring...
> and if injected in vivo in a young animal, it doesn't get phagocytosed.
I think you meant "OR if injected ..." -- clearly both phagocytosis and
digestion have to happen, either without the other is useless.
### Yes.
------------------------------------------
> ### A different explanation is that there is a dynamic balance between
> the influx of digestible fatty material, and the ability of endothelium
> and macrophages to deal with it. As time goes by, the balance tilts
> towards buildup, with first only occasional macrophages dying, then as
> the quality of macrophages goes down with age (and it does), there
> isn't enough to deal with plaque even if it's still digestible, also
> because of scarring, and calcification.
I disagree that this is an explanation, because it doesn't explain why
fatty streaks appear in childhood. Any process of accumulating damage
(e.g. junk like this) that is already easily detectable in early life
is by definition primary, not brought on by the misfortune of inhabiting
the same body as a bunch of other aging tissues (and thus experiencing
a tilting of a dynamic balance).
### Genetically determined obesity (e.g leptin deficiency) manifests early
in life, and yet we know that maintenance of body weight is a dynamic
balancing process, and can be tilted early or late in either direction. You
can have fatty streaks appearing early and developing very fast, if your LDL
is very high, in hereditary hypercholesterolemia, or they can develop
slower, if you have only the Western diet going against you. The balance can
be out of kilter because of hereditary, or acquired changes in your genome,
or due to non-genetic changes (like formation of insoluble aggregates). So
far we have insufficient data to answer the question of the specific
contribution of such factors in PD, AD, and, AFAIK, in most other
aging-related conditions.
------------------------
> Chinnery and Turnbull did some calculations showing that mtDNA can
> widely fluctuate and fix mutations into homozygosity if only random
> processes are taken into account.
This is one body of work regarding which I tend to have trouble being
diplomatic. Patrick Chinnery is an excellent medic, but suffice to say
that we discussed his hypothesis for accumulation by drift five years
ago, before he'd published anything embarrassing, and he's still having
trouble understanding the fundamental inconsistency of that model with
the data, viz. that it predicts that mitochondrial hyperproliferation
will precede (hence be seen in the absence of) COX-negativity, whereas
with the sole exception of the MELAS mutation (which seems to have a
special way to win) the reverse is true, we see abundant COX-negative
cells that lack any mitochondrial hyperproliferation.
### My boss, Davis Parker, likes the idea of clonal expansion, too. Why do
you think COX negativity must precede hyperproliferation if this hypothesis
is true?
------------------------
> A mutational ratchet mechanism tends to favor mutated DNA's in
> a 3 to 1 ratio, but this is not a selective advantage.
I don't know what underlies your arrival at this ratio, but one can get
any ratio one likes with suitable assumptions about rates of mutation
and turnover.
### I meant that in the absence of a selective pressure, any sequence tends
to randomize, and for every non-mutated nucleotide there are three ways of
mutating it, so you end up with a 3:1 ratio of mutated sequences for each
base that undergoes mutations.
-----------------------------------
The most general argument in favour of selection, though,
is that we know roughly the mitochondrial half-life (a week to a month
in rats) and thus we know how many mitochondrial generations it takes
for cells to be taken over -- and it's very, very few, probably only
a few times the theoretical minimum of log(2) of the number of mtDNAs
in the cell. Drift won't do that, whatever the assumptions.
### If the effective number of mtDNA genomes undergoing replication is
smaller than the total number of mitos, then drift can occur pretty fast.
--------------------------------
> Actually, once you have mitofection, there are at least two feasible
> methods to select the mutated mtDNA's out of the cell. Previous
> attempts failed because of lack of the ability to introduce DNA into
> mitos, but this has now changed.
Your turn to lose me. What are you suggesting, in detail?
### Well, one is an idea that is undergoing preliminary testing now, the
other is an idea that evolved in our lab had recently, but was not tested,
so I am talking about highly speculative issues. I really can't discuss the
details.
Rafal
This archive was generated by hypermail 2.1.5 : Tue Apr 29 2003 - 11:37:38 MDT