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

Robert Bradbury bradbury at sftwks.UUCP
Sun May 10 14:32:16 EST 1992

In article <9205081823.AA27075 at rust.zso.dec.com> french at RUST.ZSO.DEC.COM writes:
>> This means by the time you hit 80 ... then every cell in the body 
>> has a gene suffering a loss of function due to DNA damage!  
>So, I would like to see some speculation on
>the error correction mechanisms that you might include in the genome
>of an immortal being.
>Some of the problems that you might want to address are:
>   * Would it be better/easier to slow the aging process or to
>     freeze a person's age?

Slowing the aging process implies you are still aging.  Freezing your age
implies that you can't reverse the process.  I am going to assume that
once we understand these processes we should be able to set any age we
want.  Some might want to appear older ("wiser"?), some might want to
appear younger ("more attractive"?).  It will throw our current social
structure out the window because people will not be what they appear.
If we assume that sometime between 20-25 is optimal as far as
physical/biological fitness then that is the age I suspect most would
end up at.  However if you want to learn a foreign language you might
want to push your brain structure/activity back to your early teenage
>   * How would such error-correction mechanisms handle normal 
>     differences in the DNA of somatic cells, such as gene 
>     expression and gene amplification?
I'm not sure I understand the question.  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, e.g. people who like
sprinting would choose all the fast-twitch muscle fiber genes
while those who like marathons would choose the slow-twitch muscle
fiber genes.   Once the current problems are worked out companies
could develop "off-the-shelf" genes for $10-50K I would guess.
You could probably purchase these for a few hundred to a few thousand $.
Error correction would be a much less important problem when you
can replace any "broken" part with a new and improved version.
However, if you wanted to build yourself a huge reserve capacity
you would produce vectors containing sets of genes for specific
biochemical pathways (say the Citric acid cycle) and give yourself
4 or more of them (rather than the two copies we now typically have).
Since most gene production is feedback inhibited or requires specific
promoters in most cases having extra copies of genes should not be 
a problem.  We normally have many extra copies for some critical genes
(tRNAs, rRNAs) so it is clear that nature has taken this route before.

I do not believe that gene amplification which normally involves making
extra DNA to serve as a substrate for transcription is known to occur
in mammals.  The examples I can think of are Drosophila polytene chromosomes
or Xenopus oocytes.  If anyone knows of mammalian examples, please enlighten us.

>   * How can you preserve the state of a person's DNA without
>     also turning off vital functions such as the immune system?

I'm assuming that you feel that turning on the immune system response
means destroying the state of the DNA.  This isn't really true.  The
immune system is designed to be turned on when stimulated by foreign
substances and will turn itself off when the stimulatory factor is removed.
Many genes are turned on and off in response to external signals which
do not involve "destroying" the DNA state.  In fact since "active" DNA
is preferentially repaired over "inactive" DNA turning genes on is a
good thing.

There are a few cases where the immune system and DNA interact negatively:
  1) The enzyme(s) involved in shuffling the DNA responsible for antibody
     specificity have been potentially implicated in rarely shuffling DNA
     unrelated to the immune response.  Fortunately these enzymes are turned
     on only in maturing white blood cells and the sequences they recognize
     and shuffle are rare.  This does mean that some people will be prone
     to getting leukemia, but this is already fairly curable.
  2) Your immune system will remove cells which exibit infection by a virus,
     indicated by the presentation of unfamiliar molecules on the cell surface.
     This can also be a problem if genes used in gene therapy are too different
     from the normal genes they replace.
     So, the solutions would be:
	a) prevent viral infections, probably with vaccines
	b) make the immune system tolerate non-harmful viruses
	c) allow cells to be killed and replace them with non-infected cells
  3) Excessive response to harmless substances (pollen, dust, etc) by the
     immune system causes inflamation which leads to excessive release of
     oxygen radicals leading to DNA damage and cell death.  In this case
     the immune system needs to be trained to be unresponsive to some
     substances.  Although we do not understand the process well enough
     to do this now I expect we will in the near future.

Robert Bradbury			uunet!sftwks!bradbury

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