To
anyone who read part one and is somewhat unclear, the theme of this
series is that appearances are deceptive and all that glitters is not
gold. We have all heard stories in which a rope is mistaken for a snake
in poor light. The message of my series is meant to show that truth is
stranger than fiction.
As children we all played with a kaleidoscope and every turn produced a
new design, The glass beads remain the same in color and number but
their rearrangement viewed through a prism yields a different design.
Constitutional isomers are like that. The subtlety is that identically
connected atoms give stereoisomers which are enantiomers,
diastereoisomers or cis-trans isomers. These are handled differently by
living organisms which show preferences between right and left sided
compounds. In future articles we will try to show that we and the
universe also have a chirality or handedness.
To understand the puzzle of Prions we need to know that the basic
molecules of life capable of faithful copying with rare mistakes, are
the nucleic acids RNA and DNA. While RNA may have been the earlier and
DNA the newer molecule, these both can be mutually copied from each
other. The virus for HIV and other primitive viruses use RNA molecules
for their genetic code. When they infect us they hijack our cellular
machinery and synthesize a DNA molecule using their own RNA as a
template. On the other hand our cells normally make RNA copies of our
DNA and send them to organelles called ribosomes where they are used as
template to make corresponding proteins which are a chain of
amino-acids. The RNA to DNA and DNA to RNA both involve nucleic acids
and the process is called transcription. In other words the language of
both is the same but it is like one message is written in italics and
the other in block letters. This process is reversible. When RNA is used
to make a protein, the language is amino-acids and is different, so this
process is called translation. Crick who discovered DNA and its
functions with Watson propounded a classic dogma that one can go to
proteins via RNA from DNA, but the return path from protein to nucleic
acids is forbidden and not traversable. Thus any infection by viruses or
bacteria or infestation by parasites require them to insert a copy of
their nucleic acid genome into the cells of other living organisms.
There is a Prion disease of sheep called Scrapie in which infected sheep
scrape their hide to quench an itch and develop unsteadiness and brain
degeneration. Two separate Nobel prizes were given to Gajdusek of NIH
and Prusiner of UC San Francisco for their work on Prion diseases. There
is a CNS disease called Kuru which is prevalent in the Fore people of
the central highlands of New Guinea. They indulge in ritual cannibalism
of killed enemies and some dead relatives. The men tend to eat the
meatier parts while the women and children end up eating the less
desirable parts like the brain and spinal cord. Gajdusek noticed a
disproportionately high incidence of the disease amongst women and
children and made the connection that the transmission was by consuming
diseased nervous systems.
An earlier occurrence of another degenerative nervous system disorder
called Creutzfeld-Jakob disease in children who had received growth
hormone injections and some adults who had received corneal or other
allo-grafts helped to clarify another mode of transmission. In those
days human growth hormone injections and transplanted grafts were
obtained from cadavers. This disease causes the brain to show multiple
holes like a sponge and is known as a spongiform encephalopathy.
Interestingly very rare cases of CJD are inherited in families as is
another prion disease called Fatal Familial Insomnia. Finally the recent
epidemic of mad cow disease called Bovine Spongiform Encephalopathy and
its transmission to the British public by eating tainted beef, led to an
investigation. The epidemic was traced to diseased sheep offal including
brain that was ground into meal and used as feed for cattle. The
unrestrained greed of capitalism and free markets without regulations
and supervision becomes a conspiracy to harm or defraud the public as
remarked even by Adam Smith, the father of capitalism.
It was Prusiner’s pioneering work that showed that the infectious
material that transmitted the Prion diseases did so after irradiation,
denaturation, boiling etc and may be a protein and not a nucleic acid.
So far no nucleic acid material has been shown to be present in the
infectious material. Furthermore it is now shown that a gene present in
us makes the identical protein found in infectious Prion material. In
some instances the amino-acid composition of the genetic and Prion
protein are identical but their structure as visualized by X-Ray
diffraction etc. is different.
Proteins are a chain of amino-acids with bonding by the CO-NH links. The
protein spontaneously assumes a tertiary three dimensional structure
depending on the charges on its constituent amino-acids, their
hydrophilic or hydrophobic structure and other covalent and or ionic
bonds formed with neighboring atoms. The normal protein has alpha
helixes and the Prion protein though in some cases identical has beta
helixes and seems to change the configuration of the normal protein to
its abnormal form by serving as a template. The abnormal protein is
insoluble, precipitates, accumulates and is toxic and leads to cell
death. Different Prion proteins have a predilection for proteins of
specific cell types and parts of the brain and thus cause distinctive
symptoms. Here is another case of two identical chemical structures and
order of atoms results in different tertiary structures, one of which is
healthy and the other leads to fatal disease. Prions are a form of
protein isomers in the sense that they have identical composition and
structural order but different configurations in three dimensions.
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