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Old 09-06-2004, 02:29 PM
Bill Oliver
 
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Default Bone/ Blood Meal and Mad Cow Disease -- the answer to the challenge

In article ,
Bill Oliver wrote:

Here's a homework assignment for you. There is good evidence
to believe that most people (who are not Japanese) are simply
immune to vCJD. *One hundred percent* of people who have
acquired vCJD have one specific thing in common, which is
found in only 37% of Caucasians (and, alas, in 95% of
Japanese).

What is it? How does that fit into your calculations of
risk?

billo


It seems that the hysterics either don't know the answer, or don't want
to acknowledge it. So here it is. If, as is almost certainly the
case, vCJD is a prion disease (there are still those who think it's a
virus), then as a prion it has characteristics somewhere between a
classic poison and a classic infection. In particular, the prion does
not work by modifying DNA directly or indirectly. Instead, it is a
protein that acts as an enzyme to modify normal versions of the same
protein to work like itself. Enzymes are essentially small machines
that perform specific tasks; they are what nanotechnology wants to be.

Many poisons work in an enzymatic manner, though not to replicate but
to destroy. One famous such is ricin, a product of castor beans, that
achieved fame for being placed in a small metal bead and injected into
a Bulgarian dissident, Georgi Markov, by poking him with an umbrella at
a London bus stop. Ricin enzymatically modifies the RNA that makes up
the ribosome in a cell which is part of the machinery of translating
information in DNA into cellular constituents. Since this is
essentially a mechanical effect, the ricin is not destroyed and can
affect another ribosome, until the translation machinery of the cell is
destroyed and the cell dies. Since it just keeps moving along like a
little machine, one molecule of ricin inactivates up to 1500 ribosomes
per minute, and can kill an entire cell. Many of the lectin poisons,
such as ricin, abrin, and modeccin work in similar ways.

The prion in vCJD is another such little machine. It is a malformed
version of a normal cellular protein and instead of breaking apart
cellular components, works by changing the normal version into the
malformed version, which in turn changes other normal versions, etc.
The interesting thing about how it works, though, is that instead of
modifying the structure of the normal version, it modifies the
*shape.* Enzymes work in a way analogous to a socket wrench, and
fitting the substrate to the enzyme is a function of charge and shape,
among other things.

The interesting thing about the prion structure is that the normal form
may work in a way proposed by some people thinking about organic
computers -- having one molecule shaped in one way for a "0" and
different shape for a "1." This is a good way to do things because
these conformational changes can be very fast and it means that each
molecule can contain one bit of information.

Recent research suggests that the normal form of the prion protein may
work in a similar way -- that the change in conformation (shape) of the
normal protein is a way of making memory. See: HELEN PEARSON, Prion
proteins may store memories: Study hints at vital job for two-faced
proteins. Nature, 30 Dec 2003 for a short review or Si, K. et al. A
neuronal isoform of CPEB regulates local protein synthesis and
stablizes synapse-specific long-term facilitation in Aplysia. Cell,
115, 879 - 891, (2003). for the full article.

Thus, the action of the malformed prion protein is similar to the
normal mechanics of the normal prion protein -- to change shape under
certain circumstances and to encourage surrounding prion proteins to do
likewise. This may well be an example of the cellular machinery
that we use to create memory going bad.

But if the enzyme works a little like a socket-wrench, what would
happen if you changed the shape of the substrate? The enzyme would
either work less well or not work at all. Even though the hysterics in
this group refuse to believe that classic CJD is related to variant CJD
(vCJD), in fact studies with CJD are illuminating. It turns out that
if you take the prion protein and change one amino acid, you make it
resistant to the malformed prion's attack. If it is partially
resistant, then you increase the time it takes for the patient to
become symptomatic. If it is completely resistant, then it is, well,
completely resistant. If you change it a different way, you make
the victim more susceptible.

Normal populations have multiple forms of the same enzyme -- some work
better than others, but mutations along the way have caused some
diversity. Since we have two copies of each chomosome, some people
have two copies of the same version, and some have one copy each of two
versions. This genetic variation, called polymorphism, is the basis
for much of what is called "DNA fingerprinting" for identification.

Enzymes are proteins, which means they are largely strings of amino
acids all folded up. Two common variations of the prion protein is to
have the amino acid valine at one position (coded for by the genes of
codon 129) and the other is to have a different amino acid called
methionine. Since we have two copies of the gene, a person can have
two copies of the methionine version (MM), one copy of each (MV) or two
copies of the Valine version (VV). Interestingly enough, this gene is
associated with other wierd things -- mutations of the prion protein at
codon 178 are associated with Fatal Familial Insomnia, for instance.
Gerstmann-Straussler-Scheinker syndrome, related to Alzheimers, is
associated with mutations at codons 105, 117, 145, and 198. Cerebellar
ataxia is associated with mutations at codon 102. Alzheimer's patients
often have mutations at codon 200.

It turns out that *all* of the people who have acquired vCJD are
homozygous for *one* version of prion protein -- they are "MM" at codon
129. *No* person who is MV or VV has contracted mad cow disease.

The good news is that only 37% of Caucasians are MM, though over 90% of
Japanese are MM. The bad news is that people who have valine (MV and
VV) may be resistant to vCJD, but are *more* susceptible to Alzheimers,
and Down's Syndrome subjects who are MV or VV have an accelerated
decline in cognitive function when compared with MM subjects.

For the purposes of the Mad Cow hysteria, however, it may well be that
most people are resistant.


billo

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