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Speculation on error correction [Re: The fountain of youth.]

french at RUST.ZSO.DEC.COM french at RUST.ZSO.DEC.COM
Mon May 11 13:52:13 EST 1992


> Once gene therapy is an off the shelf process you will be able 
> to replace any of your alleles with the "optimal" one for your 
> lifestyle ...

How can broken genes be replaced without also messing up the gene
expression state of somatic cells?    For example, if my insullin 
producing gene is broken, I want to replace it and have the 
new gene turned on in my pancreas but turned off elsewhere.

In any event, you would probably have to replace all of your genes
periodically (assuming that every cell in the human body contains
a broken gene by age 80).   I find it difficult to see how it would
be possible to replace your entire genome without also disrupting
the gene expression state of your somatic cells.

Furthermore, I suspect that the easier route to immortality will be 
to prevent DNA errors from accumulating by building more sophisticated 
error correction machinery into our cells.  

Meiosis seems to provide the right model for how we might engineer
such a DNA repair mechanism.  The following excerpts on
recombinatorial repair and meiosis from the  text "Aging, Sex, and 
DNA Repair" are interesting:

PG. 255.
    (1) Resistance to a DNA-damaging agent is considerably greater
    when two chromosomes are present than when just one is
    present.  (2)  This resistance is diminished by mutations 
    in genes required for recombination. (3) DNA damaging 
    agents increase recombination.  (4) Mutants defective in
    repair pathways other than recombinational repair have
    increased levels of recombinations.

PG 259.
    We consider that unrepaired DNA damages in gametes have a unique
    cost that justifies the investment in producing them through
    meiosis rather than mitosis.  A parent contributes only a 
    single gamete to each progeny, and this cell must be as free as
    possible of DNA damage.  No other type of cell in a multicellular
    organism so directly determines reproductive success as the 
    gamete.  In general, this simple fact explains the position in
    the sexual cycle of meiosis, a uniquely powerful repair process.

PG. 259.
    Provisioning the eggs with metabolic products to be used by the
    developing embryo involves considerable metabolic activity,
    which produces oxidative free radicals as by-products.  These,
    in turn, would cause DNA damage.  Thus, the common strategy
    of provisioning the egg may increase DNA damage and as a 
    result may increase the need for DNA repair.  Consequently there
    is a special adaptive value of meiotic DNA repair during
    oogenesis.

- Larry French       





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