A Replicating Viral Journey, though a Hepatocyte
In this chapter
we are going to go on a genetic field trip.
We will become
micro-geneticists, enter a liver cell, and watch how the virus operates.
We will have
to be shrunken down to the size of a virus - approximately 50 nanometers.
As we enter the blood stream note that we must elude the white blood cells. If one of you readers are swarmed by a group of macrophages then "you're on your own"! As we arrive into the liver notice how it resembles a suburban neighborhood. Major routes of blood transportation branch into smaller ones, that branch even further. The liver is a strange and wonderful organ that is yet to be fully understood. Each liver cell is actually a small liver in itself. Each house in suburbia looks pretty much the same, well the liver cells are all exactly alike. The cells are connected by a communications network (apoptic) that is not fully understood.
When a liver cell dies the other living
cells divide and quickly replace the dead one. When many cells die, and
there are only a few scattered cells remaining, this communications network
announces "grow!". The cells somehow know that they must increase their
rates of growth and cellular division, dramatically. The little liver cells
try "mightily" to keep you alive. There is a point reached that they can
no longer do their jobs, as
functioning liver cells, and they begin
to die, also. Before they die they multiply rapidly to compensate for the
body's needs. As the neighborhoods
are destroyed, so are the roads that supply them. The supply of oxygen
and nutrients can not reach the "neighborhoods"
or individual cells (houses). It eventually becomes like a city being supplied
by one dirt road - into and out of the city. The city would soon be strangled
to death with traffic on this roadway. This is comparable to "portal" back
pressure. The main "Interstate" highway into the liver is called the "portal
artery". If your portal artery becomes clogged, or backed-up with pressure,
then then the city (your liver) will rapidly deteriorate and die. We can
not live without our livers. We need them to fight disease, store iron,
build lipo-membranes, destroy old un-used parts and reconvert them into
good building blocks for protein manufacturing use. The liver also stores
"ready energy" for the body in the form of "glygogen". Glycogen is just
the molecule that is the body creates in order to store sugars in the liver.
The liver is also involved in a host of other functions that provide life
support - to you.
Nutrient rich blood from the digestive
tract flows through (profuses) the liver like a filter, or sieve. The blood
flows from the stomach and intestines
through the liver and then back up to the heart, over to the lungs- gets
rid of bad carbon dioxide and then picks up good fresh oxygen. The oxygen
is then brought back to the heart and back out to the body again. We will
follow the blood vessels through the liver and turn to the left, here,
and go over to this side area. As we pass neighborhoods it appears that
each block is having a block party. "Hepato-citizens" are scurrying in
and out of the cells with objects in and all about. It appears to be chaos!
But the closer we look, we see that, all is actually very well organized!
Every worker in the cell has only one job to do. Each worker is designed
and trained to do only one job. They bring one object in from the blood
stream to the cell and then come and get another object to bring in. Or,
they bring an object out into the parade (bloodstream) and release it.
Away it flows to the heart. We go from large neighborhoods into smaller
and smaller ones. Finally, we reach a single block of cells and we find
one cell to our liking. It looks like an octagonal fish tank. One by one
we slip tightly through a hole in the cell membrane wall and while holding
hands proceed in a single file as we enter.
As we enter the cell make sure to let
the "guard molecules" see your "identification" or they will not let you
in. If you lose it once inside they
may not let you out! Again, "you'll be on your own" once more! What we
see
inside the cell resembles a huge construction
site. There is constant building and demolishing going on
around us. There are hundreds of new
structures being built by crews of workers. Some structures are almost
completed and others are in varying stages of completeness. In some areas
they are simply restoring old structures, and in others, they are right-
out breaking and smashing them up. There are supervisors running around
instructing workers, and trucks of supplies keep coming from the center
area of the cell site. We head to the center where the nucleus is. You
can tell that the big boss is in there, it looks like a Corporate Headquarters!
As we approach the wall of the nucleus we see a HBV DNA Virus knocking
on the door of the nucleus wall. Like "Dorothy" from the "Wizard of Oz"
banging on the city of Oz's front door. The virus does not know the secret
code word, but we do! We whisper to the HBV virus, "tell them Adenovirus
sent you". At that point another virus materializes from behind the nucleus.
"Who Called my Name?" the Adenovirus bellows! The HBV virus says, "me!" The adenovirus looks at HBV and recognizes and old friend!
"B !, you're back! and you look a little different this time." The Adenovirus compliments the HBV on its "yellow" radiance.
Remember this HBV has a friend with
it. But the friend is very angry. Apparently the friend "C" has been tied
up for decades. Once released the virus
will make up for all its inactivity over the last half century. The last
half of the American Century.
The Adenovirus has manners. It escorts
us (transport RNA) into the nucleus one by one, and closes the door
behind us as we enter. Notice that
once in the Headquarters you can see out into the cytoplasm. From the
outside you could not see into the
nucleus. You can watch all the activity from inside here, as the big boss
does. You notice a huge set of "blueprints".
They contain all the instructions for the activity going on in the
cell. We get a quick tour of the cell
nucleus before there is a problem. A hostage situation is developing. It
appears that HBV's friend, Yellow Fever,
has escaped as a mutant and is holding the big boss hostage. The
Adenovirus is in on this. The adenovirus
forces HBV into the blueprints (HBV integrates into the DNA genome
of the liver cell). Adenovirus is a
brute! It rips the HBV zipper wide open, exposing both sides of the zipper.
HBV can do nothing, it is stuck in
the blueprints.
All liver cell workers can now tell
that the big boss is in trouble by the wailing siren resonating throughout
the cell. The Alarm has been triggered by a bodyguard (messenger RNA) for
the big boss (the entire human DNA genome, or: chromosomes). The nucleus'
workers see the big boss in trouble and they do what ever the
Adenovirus says to do! Adenovirus orders
the nucleus cell workers to start grabbing "nucleotide" building
blocks and to "reform" each side of
HBV's open zipper. This they do quickly. The blocks are lined up in a row
all long the two edges of the zipper
ultimately creating "two zippers". The newly created zippers are then
ripped off again (encoded) and taken
to the cytoplasm. They are inverse "copies" of HBV. Once in the
cytoplasm, more Adenoviruses surround
the newly formed copies. They beat them up and tie them together.
Now the "string of Nucleotides" is
ready to be copied. But it is not very stable. It was not created through
millions of years of evolution. It
has not been "hardened" to the real biological world. Adenovirus now instructs
cytoplasm assembly line workers to start manufacturing (encoding) the virus!
This they also do quickly.As the virus is produced (another zipper is formed)
other workers are instructed to pull the zipper apart again completely.
Once this happens a new creature is formed. A Frankenstein monster of sorts.
A man made virus. A genetically engineered RNA sequence. When Frankenstein
appears it scares the adenovirus into working for it now. The new virus
tells all "call me HCV"!
HCV forces the cell workers (messenger
RNA) to make many copies of itself quickly, so fast in fact that a few
are made wrong. These wrong copies
(mutants themselves) continue to have reproductions done of
themselves, compounding the errors
- genetically. Over the period of ten orr twenty years many mutants,
variants, or quasi-type species arise.
Some move to other parts of the body to setup housekeeping. Some
move into the joints, others into the
sinuses, and still others float around causing trouble (gang-related
problems). The viruses leave the cell
by budding out and then entering neighboring cells (a neighborhood riot
begins). The entire area starts to swell with activity, onlookers, and
riot police. Eventually the entire liver will swell, or become inflamed.
This is the first "stage" of liver disease.
When the cellular alarm was triggered
Interferon police were called in. Remember Interferon is produced in the
liver cell, it was one of the construction projects that we saw being built.
Gamma Globulin, or Gamma
Interferon are one in the same. They
are the cytoplasm's cellular line of defense "police". However, they only
can arrest HCV. They do not know what
the "variants" look like, and remember everyone has only one job to
do in the hepatocyte. The mutants are
"undercover" viruses. They escape detection by many immune police
because of their ability to change
disguises and become different looking creatures - but still "Frankensteins"!
We must leave the cell now, as you can
see they are very busy in here fighting this virus. We will exit this way
into the blood stream and be carried
to the heart. From the heart we'll go to the lungs and then back to the
heart. We know there is a deep cut
in the finger tip of the left hand, so if we move quickly we will be able
to
exit there. Hold on!
Alright, we are safely out now and have returned to our normal size. Just one more thing folks before we meet again in Chapter 9:
Adenoviruses end up killing virus-infected
hepatocytes. Adenovirus is a "respiratory" virus, so it is out of it's
element here in the liver. It acts like a raging bull in a fine china shop.
The eventual destruction of the fine china can be predicted. The same is
true of Adenovirus in liver cells. Recently Researchers have learned to
breakup Adenovirus into a smaller Adenovirus - called a safe vector. Adenovirus
has approximately 9,000 nucleotides. The newer "safer" vectors are approximately
7,000-8,000 nucleotides long due to the "deletion of the E-3 region of
the virus". The E-3 region is like a gun in the Adenovirus' hand that is
held to the big boss' head. It makes everyone work faster and harder. Recently,
researchers have learned to beneficially use this safer "gun-less" adenovirus.
Besides, it does have manners. Because of this safer "civil" Adenovirus,
many great advances in medicine and modern genetics have been realized
recently.