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The Science of BNY217
DNA (deoxyribonucleic acid) is like this: Each cell contains DNA. DNA is
made of repeating units (nucleotides) containing three things: a sugar, a phosphate, and a
nitrogenous nucleotide base. There are four different kinds of bases: adenine, thymine,
guanine, and cytosine. They are abbreviated A, T, G, C. A piece of DNA as we picture
it (the double helix) is actually two molecules of DNA, not one. Each molecule has a
sugar-phosphate backbone facing the outside and the series of bases facing the inside.
One molecule is a complement to the other. Each A on one strand is linked by hydrogen
bonds to a T on the complementary strand, each T to an A, each G to a C, and each C to a
G. Hydrogen bonds are very weak and can be easily broken by heating.
Each double-helical DNA codes for the production of various amino acids (more
specifically, each codon (a sequence of 3 bases) codes for one of 20 amino acids).
Amino acids form polypeptides, which in turn form proteins. It’s too dangerous to use
the DNA directly for manufacturing amino acids (plus it wouldn’t be very efficient), so a
work copy of it is made through the process of transcription. The DNA is transcribed to
form RNA, which differs from DNA in that it has a slightly different sugar in the
backbone, and the base thymine is replaced by the base uracil. Only one strand of the
DNA can be read for protein synthesis (called the “sense” strand). The “anti-sense”
strand, is the complement of the sense strand. (I don’t think people really refer to DNA as
being “sense” and “antisense"—the strand that codes for protein is more often called the
“template strand”.) Therefore, the anti-sense side is transcribed to create the RNA (RNA
is synthesized by building the complement of whatever is being duplicated - it makes the
sense strand based on the anti-sense strand). mRNA molecules (the kind of RNA created
through transcription) can live hours, days, or weeks.
Not all genes are expressed and they are not always expressed to the same degree.
DNA methylation is one process that determines if a gene is silent or active. A gene can
be up- or down-regulated (amplification means to have more than one copy of a gene in a
cell) to code for the production of more or less of a protein. This can be done naturally of
artificially (by geneticists). Methylation is the addition of methyl groups (-CH3) to bases
of DNA after DNA synthesis. The base is usually cytosine; about 5% of the cytosine in
eukaryotic DNA is methylated. Highly methylated DNA is generally inactive. Drugs
that inhibit methylation can induce gene reactivation. There is a theory: Gene
methylation in many cells reinforces (or makes permanent) the differential expression of
genes that characterizes cell differentiation. In some cases, methylation patterns are
inherited through cell division. Increases in gene expression can be caused by other
factors. Sequences of DNA that code for increased or decreased transcription can be
inserted upstream of a gene (this can happen naturally in the cell, though it can lead to
cell malfunction).
(Actually, the entire process of cell reproduction is the cell cycle. Mitosis is the
part during which the cell physically divides. Replication is a separate part of the cell
cycle, and must be completed accurately before the cell gets the OK to go through
mitosis). The process of cell reproduction is called mitosis (except in sex cells; that’s
called meiosis, but we’re not going to get into that). However, before a cell can divide,
the DNA must be copied or replicated so that the two daughter cells will both have a
complete copy of all the genetic material. Enzymes (an enzyme is a kind of protein)
called helicases unwind the DNA helix to facilitate the advance of sequence-reading
enzymes (DNA polymerase) that build strands complementary to those that were
unwound. During replication the DNA can only be read in the 3’ (read as “three prime”)
to 5’ direction (It’s more correct to say that the DNA polymerases that make new DNA
strands will only work in the 5’ to 3’ direction, which is why DNA is built in that
direction.)(The five carbons of the backbone sugar molecule are numbered one through
five. The sugar-phosphate backbones of the two halves of the DNA double helix run
antiparallel to (upside-down when compared to) each other). So the new DNA strand is
built in the 5’ to 3’ direction. Of the original two DNA strands, the one with the sugarphosphate backbone running in the 3’ to 5’ direction (this is the anti-sense side, by the
way) is replicated in a continuous piece and is called the “leading strand.” The other half
of the template would require building a DNA strand in the 3’ to 5’ direction, which is
not possible, so this strand is made by synthesizing little 5’ to 3’ fragments at a time
(called Okazaki fragments) and then joining them together (picture this working like
backstitching in sewing). This half is called the “lagging” strand. Replication doesn’t
start at one end of the DNA molecule and run straight through. There are replication
forks (they look like bubbles) that form at many sites (hundreds or thousands of them)
along the DNA strand and eventually meet to form the completed new DNA strand.
Also, replication takes place in both directions along the fork (this is the leading and
lagging strand synthesis). At the end of the replication process, the cell has produced two
copies of its original DNA and is now ready for cell division.
Telomeres are the caps at the end of chromosomes. They function to prevent the
ends of the strands of DNA from fusing together. They also prevent degradation of
useful DNA information. Every time a chromosome is replicated, the DNA polymerase
mechanism stops several hundred bases before the end because replication of the lagging
strand requires some DNA ahead of the sequence to be copied to serve as a template. If it
weren’t for the telomeres, important genetic material would be lost every time a cell
divides. Telomeres are made of repeated stretches of DNA that don’t code for anything.
In humans, that sequence is a string of TTAGGG repeated between 250 and 1500 times.
Between this string and the part of the chromosome that codes for things, there is an
additional string between 100-300 kilobases in length that contains other telomere
associated repeating patterns.
Telomeres can break off due to radiation, oxidative damage (free radicals), etc.
When this happens two strands of DNA can fuse together, causing cellular instability in
the newly divided cells (because they now have either too much or too little genetic
material). If the cells do not die, the chances of them becoming cancerous are very much
increased. Scientists assumed that DNA ends could never fuse together so long as the
telomeres were attached. A few years ago they discovered that this was not the case. In
(mouse) chromosomes lacking DNA-PK (DNA-dependent protein kinase, a repair protein
that fixes places along a DNA strand that accidentally break), chromosome ends could
fuse together even with their telomeres in tact. It turns out that DNA-PK is always found
hanging out around mammalian telomere sites. The repair proteins (formerly presumed
to only show up when a chromosome needed fixing) are necessary to help the cell
identify the telomeres as natural ends and not broken points in need of fusing.
DNA polymerase can’t initiate a DNA strand from scratch. It can only work from
an already existing correctly paired series of nucleotides. In DNA replication,
nucleotides are added to an existing RNA primer molecule, which starts out about 10
nucleotides long (this is only true of lagging strand synthesis). Later the RNA portion of
the newly created strand is replaced by a DNA version. Remember the lagging end of
DNA? It is created like backstitching in sewing. The DNA polymerase must work off a
fragment that starts upstream of where the replication fork is located. When you get to
the end of the DNA strand, this is impossible, so it ends up just stopping short.
THAT’S WHY TELEOMERES SHORTEN EVERY TIME A CELL DIVIDES?
Yes. WOULDN’T ONLY THE CELL THAT ENDS UP WITH THE DNA CREATED
FROM THE LAGGING STRAND END UP WITH SHORTER TELOMERES? DNA
replication and cell division occur at two different points in time. Theoretically, what
you’re saying is correct, but every time the cell divides the telomeres will get shorter.
And as each of the daughter cells divide, their telomeres will get shorter. So it’s an
ongoing shortening, as you say below.
Telomeres get shorter through normal replication. Eventually the telomere
becomes too short and the cell stops dividing, ages, and dies (or rather than being allowed
to just age and die, a tumor suppressing gene (p53) senses when a cell’s telomere is too
short and tells it to die right away). There are very good reasons for this self-destruct
mechanism. The longer a cell is around, the more time it has to accumulate damage from
radiation, oxidation, mutations, etc. It is better to have those damaged cells die than to
turn into cancer or cause other problems throughout the body. They also might die when
the telomere becomes too short because the genetic structure becomes unstable (just as it
would if the two complementary strands fused together as mentioned above, only both of
the offspring cells would have too little genetic information). Genetic rearrangements
happen during cell reproduction of cells with no telomeres.
A particular gene is responsible for regulating length and stability of a telomere.
(However, there are a bunch of genes that produce regulatory proteins that regulate that
gene. It would be better to say that the regulation of the length and stability of the
telomere is regulated by a complex assortment of interacting proteins.)
When cells age, we age. Wrinkles, for example, are caused when skin cells stop
dividing and age. It seems that aging is nature’s way of fending off cancer. A normal
cell will divide 20-50 times before it starts to age. (IS THIS 20-50 TIMES INFO
CORRECT? I think it’s an OK generalization to say that a cell will divide 20-50 times
before it stops (senesces). It seems that the number of times a cell divides is dependent
on its environment and its age. Cells from a human fetus will divide about 50 times
before they stop, cells from an 80 year old will divide about 30 times, etc. Also, different
cells in the same population will divide a different number of times and the mechanism is
unclear. This whole topic of cell senescence is not well understood.)
Other studies say that telomere shortening itself causes the cancer, rather than
prevents it.
Telomerase extends telomere length. It is a specialized reverse transcriptase (a
reverse transcriptase is something that can create DNA based off an RNA template).–
they carry an RNA template for the telomere sequence within them (DO THEY ONLY
CODE FOR THE TTAGGG PART, OR DO THEY ALSO REBUILD THE PART
THAT COMES BETWEEN THIS SEQUENCE AND THE DNA THAT CODES FOR
THINGS? They rebuild the telomeric sequence. I believe a certain DNA polymerase
comes in to finish synthesizing the rest of the strand.) plus a protein component that
builds the new DNA strand. Telomerase genes are switched off in most cells in humans.
Telomerase is only present in cancer cells (This is not strictly true. Normally telomerase
is also expressed in germ cells (sperm and ova), stem cells, and some bone marrow cells)
(in other animals, telomerase is around all the time).
Telomere levels can be maintained by ulterior mechanisms as well. Though there
is a lot less knowledge as to what those mechanisms might be and how they work.
Cancer happens when cells divide uncontrollably and become immortal (cells
lose their cell cycle regulation, divide uncontrollably, and then become, in effect,
immortal). Cancer cells are the only cells in the human body that have telomerase in them
(not true—see note from above). Telomerase rebuilds the telomeres, making the cells
capable of dividing forever. These cells form big tissuey masses called tumors.
Cells with short telomeres are more likely to turn into cancer cells. This could be
because the genetic material has become unstable (this is why old people get cancer a lot
more often than young people – their cells have had enough time to accumulate a lot of
damage and mutation, and their telomeres happen to be short through repeated
replication).
There are recent finding however, that show that the short telomeres cause the
cell to turn cancerous. Abnormally short telomeres are a clue that a tissue is at risk of
becoming cancerous. However, cancer cells have abnormally long telomeres. The
mechanism by which this switch takes place is not fully understood. In one study,
abnormal telomere length was detected in 97% of cancer cases examined.
It is unclear how shortening telomeres, which should act as a self-destruct
mechanism for cells that have divided too many times and prevent them from turning
cancerous, can actually cause cancer.
Internal and external cues control cell division in healthy cells. Skins cells divide
all the time, liver cells divide only to repair damage, and nerve and muscle cells do not
divide at all (in a mature human). Cells fail to divide if they are missing essential
nutrients. Cells do divide if certain growth factors are introduced (like when platelets
fragment and release PDFG in the vicinity of an injury – triggering cell division of
fibroblasts). Density of cells is another important factor that triggers cell division or the
cessation of division. In contrast, cancer cells continue to divide even after the cells are
crowded together. They continue to multiply until all nutrients are exhausted. If and
when they do stop dividing, they do so at odd times during the cell growth cycle.
When a single cell in a tissue transforms into a cancer cell, it is usually destroyed
by the body’s immune system. If not, the cell continues to divide and the lump of
irregular cells then becomes a tumor. If tumor cells acquire the ability to invade the
surrounding tissue, the tumor is said to be malignant and the person is said to have
cancer. In addition to having a lack of control over cell division, cancer cells may have
abnormal numbers of chromosomes, their metabolism is abnormal, and they cease to
function in any constructive way. Because of changes to the exterior surface of the cell,
they also lose their attachment to their neighbor cells and can be transported by the blood
stream to other parts of the body, where they form more tumors. The spread of cancer
cells beyond the original site is called metastasis.
Mutations that alter the expression of genes that regulate cell growth and division
can lead to cancer. The mutations can be spontaneous or can be caused by environmental
factors, such as carcinogens, physical mutagens such as x-rays, and certain viruses.
Proto-oncogenes are genes that code for protein products that normally regulate cell
growth, cell division, and cell adhesion. Damage to these genes turns them into
oncogenes, or cancer-causing genes. This is done by gene up-regulation, chromosome
translocation, gene transposition (Transposons: highly repetitive strands of DNA that are
nonfunctional but can be moved to other locations along the chromosome and cause
disease, such as neurofibromatosis-1 (elephant man’s disease). A transposon could insert
within a sequence that is involved in regulating transcription and lead to increased or
decreased production of one or more proteins.), and point mutation (the change of a
single nucleotide). The same thing can happen with tumor-suppressor genes (genes
whose products inhibit cell growth). You generally need problems with more than one of
the abovementioned genes per cell in order for it to become a full-blown cancer cell.
That’s why the incidence of cancer increases with age. There is more time for these
mutations to accumulate.
Other important molecules:
rTel gene: Before replication, it untangles the knots that commonly form in DNA
(these knots are called g quartets). Mice born without this gene die 10-12 days after
birth. However, having a lot of whatever is coded for by the RTel gene (it’s a helicaselike protein) allows cancer cells to divide. If doctors were to send in a lot of RTel
inhibitors, they could stop tumors.
Tankyrase 1: an enzyme that makes telomeres accessible to telomerase. A
combination of telomerase inhibitors plus tankyrase 1 would be useful in fighting cancer.
DDX11: Differences in telomere length are linked to a region on chromosome 12.
The gene could be DDX11 (over 49% in variability of length can be explained by the
activity of this gene).
Telomere-restriction fragment analysis – used to analyze telomere length
FISH - uses fluorescent probes designed specifically for particular locations in
DNA and is commonly used to detect or confirm gene and chromosome abnormalities.
Also used to determine telomere length.
Werner’s syndrome – premature aging. Werner’s syndrome is caused by a
mutation in the WRN gene. Mutations on this gene cause genetic instability (specifically,
chromosomes become dramatically rearranged). Genetic instability also leads to cancer.
WRN is also implicated in telomere maintenance. Loss of WRN leads to accelerated
telomere shortening (thus premature aging).
Foxm1b – a gene that is not active in old age. It makes mice young and vital in
their youth. If you remove the gene entirely from the mouse, you cannot give it cancer
even if you try (however, the mouse also doesn’t get all of that nice “young and vital”
stuff) (presumably, you’d want to prevent the gene’s expression when the mouse is older,
since it’s probably required during normal development if it makes cells grow).
Pokemon (POK Erythroid Myeloid Ontogenic factor) – a cancer causing gene
that appears essential for other onco-genes to cause cancer. The pokemon protein causes
harm by repressing the function of other proteins (like tumor suppressor ARF). DOES
EVEYONE HAVE THIS GENE? I would have thought so. IT’S JUST NOT ACTIVE
MOST OF THE TIME? Since this report was just published, I don’t think anyone knows
what its normal function is. It might be expressed at low levels, or it might be regulated
by something else.
Epigenetic – The “epigenetic” components of a disease are factors that affect a
cell or organism without altering its DNA.
SIR-z and INDY-gene – genes that are being patented by the longevity company
Elixir. They have found proteins in mice that can double their life spans. They are trying
to turn these proteins into drugs that can be used on humans.
Promoters – sections of DNA that don’t code for anything but that do determine
how frequently a particular section of nearby DNA is transcribed.
Other useful facts:
There are 46 chromosomes in human somatic (not reproductive) cells. There are tens of
thousands of genes in a typical human cell; if all of this genetic material where on one
chromosome, replication would be a mess. Also, when we picture a chromosome, we
picture it in that x-shape. That is what it looks like right before the cell divides; before
that it’s all stretched out and difficult to identify by microscope.
Of the 30,000 genes in the human genome, just 67 are involved in changing normal cells
into cancer cells.
There are about 6 billion bases in a single human cell. It only takes a few hours to copy
all of this DNA. More than a dozen enzymes and other proteins participate in DNA
replication. New base pairs are added to a forming DNA strand at the rate of 50 per
second (in humans).
Errors in the newly created DNA molecule amount to only 1 in a billion nucleotides.
Initial pairing errors occur about every 1 in 10,000 base pairs, but proofreaders called
mismatch repair go through and fix things. There are more than 50 types of DNA repair
enzymes.
Hundreds of thousands of people are diagnosed with cancer per year. A lot more are
undiagnosed. A lot of people with cancer die.
Cells of the line HeLa have been dividing since 1951 (calls taken from a tumor from
Henrietta Lacks).
Adding telomerase to immune cells lets them keep dividing indefinitely (and they didn’t
show signs of chromosomal abnormalities). In AIDS patients the immune cells are
overworked and divide much more frequently than it healthy people, so they age and die
a lot earlier.
The European Shag and the wandering albatross (with the largest wingspan of any bird –
6 feet to 4 meters) are long-lived birds. Their telomeres do not shorten as adults, and
they do not get a lot of cancer. They normally live 40-80 years.
IF RNA PRIMER MOLECULES ONLY NEED TO BE 10 NUCLEOTIDES LONG TO
ALLOW DNA POLYMERASE TO START BUILDING ON TO THEM, WHY DOES
REPLICATION STOP SEVERAL HUNDRED BASE PAIRS BEFORE THE END OF
A DNA SEQUENCE? This might be because Okazaki fragments start only at specific
places on the DNA. So if the primases that make the RNA primers don’t see any
sequences they like towards the end of the chromosome, replication stops.
How the Science Works in the Script
As of 2005 there are several different companies doing longevity research.
Several of them have patents on different genes. President Bush keeps getting the United
States into unpopular wars. Social Security is having a lot of problems. There are a lot
of old people who want to retire and not enough money to take care of them all.
Insurance companies charge ridiculous amounts of money for coverage and if you have
the misfortune of actually getting sick, your premiums go way up. As if that’s not bad
enough, health insurance companies are purposely killing people so they can save money.
In the near future, thanks to government mismanagement of myriad sorts,
economy goes into recession. There is a biotech bust. Longevity research, along with all
other forms of non-chemical-warfare research, slows. Mostly unrelated-ly, the
government gives insurance companies special deals where they get a lot more control
over the health care system with little or no regulation from the government. Through a
lot of government-backed shady deals, insurance companies take over the longevity
research companies, as well as most cancer research and other medical-research facilities.
Without government funding, independent companies find it difficult to not sell out.
The insurance companies don’t want longevity research to continue because the
longer people live, the more medical attention of some kind they are likely to need. It is
too expensive for the insurance companies to have people live too long unless they are
also in perfect health. And if they’re in perfect health, they don’t need health insurance.
Insurance companies exert influence over the government (the right-wing wacko
government supports anti-longevity-research measures for its own reasons) – longevity
research is made illegal. Because the insurance companies now have control of the
patents of genes related to longevity research (and if the patent laws are structured in
such a way that the patent would expire by the 2020s, let’s assume they have them
changed), they can also cripple research in areas incidentally related to longevity
research, such as cancer research.
Around 2018 things start to get better. Insurance companies maintain their
control over most medical research, but the economy is much improved and the country
is no longer at war. The social atmosphere is one of levity. People are breathing a sigh
of relief and have started partying.
Insurance companies are pursuing their own cancer research, but they keep tight
control over their breakthroughs. The most effective treatments are also the most
expensive, and insurance companies see to it that only people who can afford them get
them. They maintain strict control over their patented genes. (Also, pre-cancer
screenings have become much more easy and accurate. Viable treatment options have
not kept apace.) Anyone wishing to find alternative cancer treatments must do so almost
entirely from scratch, since they are not allowed to use significant amounts of previously
done research.
Bunny is trying to make a cancer-fighting product that will be freely available.
He wants to start a public cancer research database (any existing ones are long out of
date). He is very guarded about his current research because he fears the insurance
companies will steal his ideas/etc and, if they reach the breakthrough he is searching for
before he does, they will patent it. He is also wary that they will find some way to take
financial control of the company for which he is working. Bunny intends, once he has
the cure, to give it to everyone. The price will not be inflated, so it will be a viable
treatment option even for those without health insurance. All of Bunny’s financers have
contributed for charitable reasons and do not expect very large investment returns. The
good guys in medical research have not disappeared, they have gone to funding smaller
independent labs such as Bunny’s.
What Bunny is working on is a synthetic protein that affects DNA polymerase by
making it capable of beginning with a sequence of three nucleotides instead of the 10 or
so it naturally needs. (This isn’t very realistic. The primers need to be about 10
nucleotides long to make the enzyme specific, otherwise instead of having replication
start at specific points along the DNA, there will be replication going on everywhere
(since the probability of a specific 3 nucleotide sequence is much higher than a specific
10 nucleotide sequence)—and that isn’t very efficient for the cell. Are you just trying to
make the polymerase more active? There are other ways of doing that.) He is very close
to perfecting this protein (which he wants to call BNY217 – CAN HE CALL IT THIS IF
IT”S NOT A GENE? Usually people like to give proteins cute names, like Pokemon.
They don’t usually name proteins after themselves—it’s not considered good form).
Then he intends to do things to the cells to induce them to form cancer and see if they
will. He believes that if he introduces the enzyme to precancerous cells (ones with
abnormally short telomeres), he can prevent them from becoming cancerous. Because
pre-cancer screenings in the future are so easy, he could save a lot of lives. In this way
he will also be able to more clearly identify the link between telomere length and turning
into a cancerous cell (at this point in the future the link has still not been figured out). He
would also do experiments where he adds the new DNA polymerase protein into cancer
cells and injects the cell with telomerase inhibitors. This way he can see if cancer cells’
immortality are linked simply to non-shortening telomeres or to something specifically
related to the telomerase. All sorts of opportunities will be opened. Obviously any use of
this DNA polymerase protein to pursue immortality research would be illegal, but it’s
okay to use it to study cancer cells. One step closer to understanding cancer is one step
closer to finding the cure to it.
***
Evi, who is fantastically independently wealthy, and his lab partner Ginger
continue their longevity research in spite of its being made illegal. Around 2010 they
find a way to clone skin cells, give them a small, initial boost of FOXm1b, and then fuse
the cloned cells to existing tissue through grafting techniques. This gives them the
appearance of being young forever. Evi, who is 60 in 2010, is so happy that he looks
young again that he starts living recklessly. When you clone a cell, the new cell’s
telomere length reflects the length of the original cloned cell’s telomere, even though the
new tissue starts out looking young and brand new. The cloned cells much more rapidly
reach a point where they start to age than would normal cells. The telomere length of the
cloned cells also reflects any time spent in culture. This means that Evi must reimplement the treatment every few years, plus the interval between needing new
treatments keeps getting shorter and shorter. By the opening of the story, the cells Evi
has remaining in culture have reached the point that once he clones and uses them, the
new cells will only last a few months before they start to age. He is desperate to use
Bunny’s breakthrough to find a permanent solution to his aging problem.
Soon after Evi and Ginger make their skin-cloning discovery, they find a way to
prolong life indefinitely. Or so they think. By removing the pokemon gene (and
compensating for any bad things that would happen through such a removal) and
methylating the DNA in such a way that telomerase is always being produced, they create
cancer-proof immortal cells (these two things are going to be very difficult to do. You
can’t really remove a gene from someone’s genome, and methylating only the
chromosomal region of the telomerase gene seems very unlikely because of the way
methylases work. A better way would be to use small molecule compounds that can
completely block the activity of the pokemon protein (or block the transcription of the
pokemon gene) and use a different compound to keep telomerase expression on (maybe
through regulation of the regulatory proteins. Everyone likes small molecule compounds
because they’re easy to administer and in theory their structures can be tweaked so that
they’re specific for only one target.)). In theory, using the same cell-integration
technique used for the skins cells, the new immortal cells could take over as the old ones
in the body died. Cells from each tissue and organ could be injected with the new super
cells (or have large stretches of cloned cell mesh grafted onto them), which in theory
could then become the dominant tissue in the body. Evi is very well aware that this idea
probably won’t work, but Ginger insists they go through with it and Evi obliges (Evi is a
surgeon in addition to being a geneticist). Unfortunately, the telomerase portion of the
experiment doesn’t work as well as expected. The cells keep dividing even though their
telomeres are too short. [This part gets a little silly.] They had been working on several
projects concurrently; another is a way to turn off the effects of p53 (a tumor suppressor
gene that tells the cell when the telomere is too short that it should die). They add some
of that for good measure. So now his genes keep dividing even though they are missing
genetic material (thanks to the fact that their telomeres are too short), and they aren’t
going to turn into cancer. So basically he keeps getting a lot of diseases. He has a lot of
growths, elephant-man type diseases, etc. (OK, this is pretty funny.) They also found a
way to mimic the effects of the Foxm1b gene, which makes you young and vital. They
figured since Ginger couldn’t get tumors anymore anyway, what the hell. They add some
of that.
***
When Evi does finally confess to Bunny what has happened to Ginger, he does so
one thing at a time. It could be really funny every time Evi says “Oh, and maybe we
kinda did some of this other thing too…” Bunny gets more and more appalled that they
would do anything as dangerous and ghoulish as what they have done.
Bunny’s DNA polymerase adjusting enzyme can’t really help Ginger in any way.
Evi lies to him towards the end of the film (after he finds out about Ginger) and says
that’s why he really wanted to be a part of Bunny’s research. Bunny doesn’t believe
him, but goes along with it just in case. At the big showdown at the end of the film,
Bunny ends up with a syringe full of the enzyme that he thinks will do something and Evi
(who by this time really is reformed) has to tell him it’s not really going to work. So
they’re stuck in a really dangerous situation with very little plan how to stop Ginger’s
rampage.
Other Notes Related to Evi’s Odd Behavior Throughout the Film:
4 nucleotides are an entire alphabet.
“The entire genetic alphabet is only four letters long. A. T. G. C.”
Evi is doing everything possible to slow his aging, but in a silly way:
He mixes his alcohol with pomegranate juice (even sorts of alcohol that you really
shouldn’t be mixing with anything).
Stress leads to higher oxidative stress, lower telomerase activity, and shorter telomere
length (by the equivalent of 10-17 years). So Evi chooses to party and not worry to
extend his life.
Caloric restriction – extends lifespan. There should be an exchange between Evi and
Bunny over this. Bunny will make a comment about how he hardly eats anything. Evi
responds that caloric restriction increases lifespan. Bunny: Not if you just drink all the
time and get no nutrition. Evi: I take vitamins.