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The Cell
Terminology
DNA and RNA
Genetic Mutations
The Cell Membrane
Central Dogma
Classes of Cells
Cell Death
Undoubtedly you have heard the phrase, “You are what you eat.” A proportion of our diet is protein and we are
certainly determined by our proteins. They shape every part of our bodies, from the composition of the smallest cells
to the largest organs.
Proteins are composed of polypeptides, which are composed sequences of amino acids. A protein is obtained by
properly folding and bending the polypeptide.
Terminology
The cell is the fundamental unit of all living matter. The major characteristics that characterize living cells are:
1.
2.
3.
4.
5.
Self-feeding or nutrition: they take up chemicals from their environment, transform them, release energy,
and eliminate waste products.
Self-replication or growth: they can direct their own synthesis, growing and forming two cells.
Differentiation: they undergo changes in form and function.
Chemical signaling (chemotaxis): they respond to and sometimes produce chemical and physical stimuli in
their environment.
Evolution: they evolve and change via natural selection to optimize their existence.
Although this may sound like an exercise in semantics, anything that does not satisfy all five of these
requirements is not a living cell.
Cells are 90% water. The remaining dry ingredients are: 50% protein, 15% carbohydrate, 15% nucleic acid,
10% lipid (fat), and 10% other stuff. The approximate chemical element composition of a cell is typically: 60%
hydrogen, 25% oxygen, 12% carbon, 5% nitrogen, small amounts of phosphorus and sulfur, and traces of other
elements.
The Cell Membrane
The cell membrane is composed of a lipid bilayer1. Each part of the bilayer is composed of structures that look
like , which has glycerol and a negatively charged phosphate group at its head and two hydrocarbon chains of
phospholipids along its tails. Each tail is hydrophobic, meaning that it avoids water, while the head is hydrophilic,
meaning it seeks water. The water-seeking heads face the watery inside and outside of the cell and the wateravoiding tails face each other. The membrane separates the wet interior of the cell from its wet environment. The
membrane is about 5 nm thick2.
An actual cell membrane has additional proteins, some of which serve as channels for the passage of various
substances.
1
2
Also called a Langmuir-Blodgett layer by physicists.
One nanometer (nm) is one billionth (10-9) of a meter.
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Classes of Cells
There are two classes of cells: prokaryotes and eukaryotes3. Prokaryotes have no differentiated nucleus,
whereas eukaryotes do have a differentiated nucleus and it is enclosed within a nuclear membrane. There are only
two subclasses of prokaryotes: Bacteria and Archaea. All multicellular organisms are eukaryotes. The average
eukaryotic cell is about ten times larger than the average prokaryotic cell. A eukaryote nucleus is shown below.
The nucleus of a cell is not a smooth spherelike surface, as the picture below seems to indicate. In fact, it is
quite convoluted, with fissures and
tunnels covering its surface. The surface
area to volume ratio is higher for the
nucleus than it is for the cell itself4. The
nuclear membrane, as shown to the left, is
not a closed surface, rather it has many
irregularly spaced holes. These holes
prove instrumental in HIV’s ability to
enter the nucleus and change the cell’s
genetic machinery.
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1. Some authorities argue that there are three separate categories: Archaea, Bacteria, and Eukaryotes. They do this on the
grounds that the name prokaryotes implies that eukaryotes have evolved from prokaryotes. In fact, eukaryotes are more similar to
Archaea than to bacteria and the evolutionary line is not consistent. This remains controversial at this date, 10/1/2010.
4
For a perfect sphere this ratio is 4πr2/(4πr3/3) = 3/r. Therefore, the larger the sphere, the smaller the ratio. The rougher the
surface, the more surface area, and the higher the numerator of this fraction.
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DNA and RNA
The cells of prokaryotes and the nuclei of eukaryotes contain DNA and RNA, both nucleic acids—
deoxyribonucleic acid and ribonucleic acid, respectively. These two chemical compounds are composed of purines:
adenine and guanine, and pyrimidines: thymine and cytosine. But thymine is replaced by uracil in RNA. These
compounds appear in complementary pairs or bases as A-T/A-U or G-C. DNA is coiled into a double-stranded
helical shape, while RNA is mostly single-stranded but not coiled. The following ball-and-stick model illustrates the
shape of DNA.
The human genome contains some 3 billion base pairs. If we uncoiled one of our DNA molecules—of which
there is one in every nucleated cell in our body—it would stretch nearly one meter!
Three consecutive bases can code for an amino acid and these triples are called codons. The codons are words
of a language. You need one codon for each amino acid. Most amino acids have several different codons, e.g., UUA,
UUG, CUA, CUC, CUG, and CUU are all RNA codes for leucine. Exons are the coding regions and introns are the
noncoding regions on DNA. The following table is a listing of the codings for those 20 amino acids that the human
body needs. The codes are like sentences that tell us how to construct the proteins.
Think of the codons as words in a (short) dictionary. Then the 20 amino acid translations listed below are their
definitions and this table is the unabridged dictionary for the language of protein production. Notice that there is also
a code word for stop that indicates when a protein code (sentence) is complete.
Amino Acid
Alanine
Arginine
Asparagine
Aspartic Acid
Cysteine
Glutamic Acid
Glutamine
Glycine
Histidine
Isoleucine
Leucine
Lysine
Methionine
Phenylalinine
©PGB
Codons for Amino Acids
3 Letter
1 Letter
RNA Codons
Abbreviation Abbreviation
Ala
Arg
Asn
Asp
Cys
Glu
Gln
Gly
His
Ile
Leu
Lys
Met
Phe
A
R
N
D
C
E
Q
G
H
I
L
K
M
F
GCA, GCC, GCG, GCU
CGA, CGC, CGG, CGU, AGA, AGG
AAC, AAU
GAC, GAG
UGC, UGU
GAA, GAG
CAA, CAG
GGA, GGC, GGG, GGU
CAC, CAU
AUA, AUC, AUU
UUA, UUG, CUA, CUC, CUG, CUU
AAA, AAG
AUG
UUC, UUU
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Proline
Serine
Threonine
Tryptophan
Tyrosine
Valine
Stop
Pro
Ser
Thr
Trp
Tyr
Val
P
S
T
W
Y
V
.
CCA, CCC, CCG, CCU
UCA, UCC, UCG, UCU, AGC, AGU
ACA, ACC, ACG, ACU
UGG
UAC, UAU
GUA, GUC, GUG, GUU
UAA, UAG, UGA
As you can see, many amino acids have multiple codes, each appropriately called a synonym. All in all, there are
43 = 64 possible codings, 61 of which code for amino acids and the remaining three carry the stop code. Each cell
uses these codes to make the amino acids available in its cytoplasm.
A gene is any connected or disconnected segment of DNA that encodes for a specific polypeptide. Thus the
gene is the set of rules for word usage that makes the language valuable for transmitting information. All proteins
are composed of polypeptides, which are sequences of amino acids5 and each amino acid has the RNA coding(s)
listed in the table above. Proteins can contain as few as 30 amino acids to as many as several thousands.
Chromosomes are constructed from genes and there are 46 human chromosomes consisting of 23 pairs, one pair
of which is either an XX or an XY chromosome (and in rare circumstances XXY, XXXY, etc., XYY, or XXYY6).
In the past, noncoding regions of DNA have been referred to as “junk DNA.” Recent research has discovered
that introns code for small segments of RNA that are not used in protein production. Some genes produce rather
small segments of RNA—21 to 23 base pairs. These are called micro-RNA or miRNA. When initially produced as
longer segments, they tend to fold over on themselves, thus creating small double-stranded RNA. These are present
in many species, including about 200 of them in humans. In yeast, micro-RNA can bind to a chromosome and shut
off a gene. Hence, some of these small pieces are called small interfering RNAs or siRNAs or RNAi. The latest
technology is to create these RNAi and use them to turn off genes related to disease. Although research is
proceeding apace, much remains to be done.
To add complication to complication, each gene of the DNA helix is wrapped around a switchable long chain
chemical consisting of 8 histones; together they are called chromatin. The condition of the chromatin corresponds
to an on/off switch. When the switch is on, the gene is expressed, when off, the gene is not expressed. For this
reason, some people with genes having a high correlation with disease do not get the disease; those genes are not
switched on/expressed7.
The first free-living organism to have its complete genome sequenced was Haemophilus influenzae in 1995.
Since then more than 800 organisms have joined the ranks of the completely sequenced. As examples, influenza
virus has 11 genes, the bacterium E. coli has 4149 genes, the simple fruit fly was found to have 14,889 genes, the
chicken has 16736 genes, and grapes have 30434 genes.
The study of the human genome culminated in what was purported to be the complete listing of the DNA base
pairs8. One result of the study was that the human genome contains a mere 223339 genes, half as many as rice! A
further surprise was that all humans share a sizable part of the basic genome 99.9%. Contrary to previous beliefs,
parents do not pass down one copy of each gene. Rather, they can give their offspring as many as ten copies of a
5
Over 100 amino acids are found in nature but only these 20 are needed for human growth. There are ten essential amino acids,
which must be obtained from food. They are isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and
valine, which cannot be synthesized by the body. Argninine and hystidine can be synthesized, but not in sufficient amounts for
growing children. Nonessential amino acids, which can be produced by the liver, are alanine, aspartic acid, arginine, citrulline,
glutamic acid, glycine, hydroxyglutamic acid, hydroxyproline, norleucine, proline, and serine.
6
XXY occurs in 20 in 10,000 newborn males births, XXYY occurs in 1 in 10,000, and XYY occurs in 3–5 in 10,000.
7
Perhaps more interestingly, almost all humans have 23 pairs of chromosomes. Males have an XY-chromosome pair and females
have an XX pair. Since each of the female X chromosomes contains 1098 genes that code for various proteins, there is significant
overlap. If both Xs were to produce their coded proteins there would be major problems. Therefore, one of the X-chromosomes is
expressed and the other is mostly (75%) turned-off, while the remaining ones are permanently activated, thus expressed at twice
the level in women as in men.
8
The DNA of humans and chimpanzees is in at least 98.5%, and possibly as high as 99.4%, agreement, while that of humans and
mice is in 75% agreement. The variability from human to human is less than the variability from chimp to chimp.
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There are currently at least three groups analyzing the human genome. The RefSeq database maintained by the National
Institutes of Health lists 22333 genes that encode for proteins, the Gencode project list 21671, and the Mammalian Gene
Collection lists 18877.
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single gene and on the other hand they need not transmit any copies of some genes10! Researchers have found that at
least 12% of the genome—that includes 2900 genes and regions between them—can differ greatly between people.
The average weight of the human genome is 3.3 picograms (pg) = 3*10-12 gram. Hummingbirds average 1.03 pg
and some salamanders have genomes whose mass exceeds 100 pg.
As far as is known today (01/01/2011), race is not a genetic factor that distinguishes between the DNA of
various people, although there is a difference in gene expression between Asian and European individuals. More
importantly, your genome is not fixed for all of your life. Change is the only constant. Mutations, jumping genes,
transposons, all contribute to this continuing variability. Even with that seemingly high degree of identity, there
remain about three to four million base pairs at which we humans can differ11 from each other.
Sidebar: Besides its many forensic uses, DNA analysis has been used to discriminate among the
various breeds of dogs. Despite what the American Kennel Club says, four basic clusters emerge:
(1) the oldest dogs, (2) guarding dogs, (3) herding dogs, and (4) hunting dogs. Some of the breeds
in each cluster are shown below.
Oldest
Alaskan malamute
Chow chow
Pekingese
Shar-pei
Siberian husky
Guarding
Boxer
Bulldog
German shepherd
Mastiff
Rottweiler
Herding
Belgian sheepdog
Collie
Old English sheepdog
Saint Bernard
Shetland sheepdog
Hunting
Airdale terrier
Beagle
Bloodhound
Golden retriever
Pointer
Central Dogma of Biology
The Central Dogma of Biology states that for all living cells:
DNA → RNA12 →
protein synthesis
The first step () is called transcription and the second () is translation. In transcription, the coding on DNA is
transcribed onto mRNA (messenger RNA). This occurs by matching base pairs on one strand of the DNA to the
mRNA as shown in the following figure. The mRNA then binds to a ribosome, where the proteins will be made.
10
This is called copy number variation. Identical twins frequently have different copy numbers in several genes. Usually the
copy number ranges from zero to five, but in rare cases it can range from 5 to 368.
11
Prior to the completion of the Human Genome Project, the philosophy of Genetic Determinism held sway. It claims that the
genome with which you are born completely determines you, from physical types, disease susceptibility, all the way to sexual
preference. But with so few genes, this theory no longer commands the attention it once did. In fact, randomness associated with
the many linkages between genes gives rise to a whole host of other, as yet unaccounted-for, factors.
12
Research published in 11/2010 showed that in white blood cells from 27 different people, on average, as many as 4000 genes
had misspellings in their RNA that was not in their DNA. In fact, RNA contained misspellings at more than 20000 different
places along their genome and about 10000 misspellings in two or more of the people studied. Why and how these occur is, at
present, unknown.
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Transcription from DNA to RNA
Transfer RNA is a small molecule consisting of only 80 nucleotides, containing anticodons13. Its function is to
deliver amino acids to the polypeptide molecules being made in the ribosome. The sequence of nucleotides forming
DNA dictates the sequence of amino acids needed for constructing the protein. During translation, each section of
tRNA links to its appropriate free-floating amino acid within the cell. These amino acids are then carried to a
ribosome. There the tRNA bonds with mRNA that has attached to the ribosome. Then, codon by codon, a chain of
amino acids is assembled into a protein.
The Central Dogma of Biology holds for all life forms found to date on this planet14, subject to the transcription
errors noted in footnote 12.
The very complex molecular structure of a ribosome is shown below.
Ribosome
Just as DNA is the master recipe for proteins, mRNA is the user’s recipe, tRNA is the collector of the
ingredients, and the ribosome is the “chef” or “kitchen,” where the language of the words coded for in DNA and
RNA is used to construct the proteins out of which all living cells are made.
A protein is a rather complex and heavy molecule15. The following is a computer-generated image of the protein
with the coded name p21 H-ras. The p21 means that it is a protein with a molecular weight of 21 KDaltons = 21,000
Daltons.
13
The anticodon to UAC would be AUG.
This is where that semantic difference for the definition of a living cell enters. Viruses do not satisfy all five requirements of a
living cell. Hence, they are not considered to be living and they need not follow the Central Dogma of Biology. But, more of this
later.
15
During conditions of starvation (and diabetes mellitus), the body draws from its amino acid pool, and not its fat stores, to make
glucose. So, long-term fasts are not a medically wise way to lose weight.
14
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Cell Death
Considering that eukaryotic cells reproduce by mitosis, doubling each cycle (the average adult human produces
(and kills) about one billion = 1,000,000,000 = 109 cells per day), if not for cell death it wouldn’t be long before
there were more cells than an organism could possibly sustain. Also, cells age and wear out; some take just a few
hours and others can last for decades, depending on the stressors encountered16. For this reason all cells carry an
inherent coding called programmed cell death. After a cell has split a certain number of times, it dies. Without the
presence of this mechanism, cell proliferation would destroy the organism. In humans, our skin cells die and slough
off at a regular rate. After a shower, take a towel and rub your arm; what you’ll see is a many celled mixture of cells
in the dead skin that is exfoliating.
There are four known forms of programmed cell death, but we will only concern ourselves with one of those.
Apoptosis is triggered by the enzyme caspase. The cell membrane softens, the nucleus shrinks and divides, and the
entire cell starts to bleb or balloon and oscillate. In short order, the cell lyses or bursts. The picture below shows a
cell beginning to bleb.
A cell beginning to bleb prior to lysis.
Genetic Mutations
The genomes of many organisms are far from immutable, some change slowly and others change rapidly. The
smallpox virus seems to have remained unchanged for many centuries, if not millennia. The influenza virus’s
genome can change during the course of a single flu season, using antigenic drift and/or shift. As we will see, HIV
has a genome that is very likely to mutate in a relatively short time. How can such mutations affect the rest of the
organism? In the following, we will look at some human mutations.
As a specific example, research discovered a genetic mutation that caused the production of steroid 5areductase. This chemical is responsible for the transformation of testosterone to dihydrotestosterone, of which the
latter is 50 times as potent as the former. In one codon, adenine (A) has been replaced by a (G) guanine. This
replacement results in the replacement of alanine in place of threonine (Check the codon table.) in the finished
protein. The end result of this single mutation is a five-fold increase in the risk of prostate cancer.
Sickle cell anemia is an inherited disease where a single amino acid substitution (valine replaces glutamic acid)
has profound effects. This alters the production of red blood cells, changing them from disk-shaped to crescent or
sickle-shaped. People who are homozygous—having that mutation on both chromosomes—have about 85–95% of
16
Noncancer cells usually obey the Hayflick limit, whereby they replicate about 50 times and then die.
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their red blood cells affected. This leads to severe anemia leading to episodes of severe pain and other serious
symptoms due to the low oxygen levels in various parts of their body. Consequently, their life expectancy is
considerably shortened. People who are heterozygous—having that mutation on only one of their chromosomes—
have about 40–45% of their red blood cells affected. They rarely suffer to the extent of the homozygous. Both forms
of the disease result in resistance to infection by the malarial parasite, indicating its likely origin in the malarial areas
in Africa.
You may have heard of the breast cancer genes: BRCA1 and BRCA2. A woman with a specific mutation on
BRCA1 was thought to have at least a 60% higher lifetime risk of developing breast cancer. In the US, that
probability is 0.13, so that the mutation would lead to a probability of 0.21. Besides that, there is a gene CHEK2,
with a fairly low mutation rate. But, if you have the mutated CHEK2, a woman’s risk doubles and a man’s risk17
increases by a factor of ten!
Defects in genes on chromosome 17 have been analyzed in some detail. The following table lists some of those
genes and their corresponding medical condition.
Gene
Rp13
CTAA2
MYO15
COL1A1
NF1
SGCA
BRCA1
GH1
SSTR2
Medical Condition
Retinitis pigmentosa18
Cataract
Deafness
Osteogenesis imperfecta19
Neurofibromatosis20
Muscular dystrophy
Breast and ovarian cancer
Growth hormone deficiency
Small cell lung cancer
The gene P53 acts as a tumor suppressor. Hence, any mutations it might experience usually result in the growth
of cancer cells21. Fully half of all cancers are thought to be associated with mutations in this particular gene.
Furthermore, there is research that shows that all cancers are the result of a small number of mutations in a set of
fewer than 100 genes.
On January 1, 2003, the complete coding of human chromosome 14 was announced. Only human chromosomes
22, 21, and 20 had been previously analyzed in full. Chromosome 14 is the longest human chromosome consisting
of 87,410,661 nucleotides, constituting about 3% of the entire human genome. It contains 500 known genes and
about 350 suspected genes. It also is home to a gene, neurexin 3, which consists of about 1.7 million base pairs. This
gene is thought to be associated with the construction of synaptic connections in the brain. Mutations on this
chromosome are responsible for over 60 diseases, ranging from achromatopsia (complete color blindness) to Usher
Syndrome. One of this gene’s mutations may cause early onset Alzheimer’s disease.
Some other conditions known to be associated with one or more genetic defects on other chromosomes are:
basal cell carcinoma, colorectal cancer, cystic fibrosis, diabetes mellitus, dyslexia, fructose intolerance, hemolytic
anemia, Huntington’s disease, leukemia, muscular dystrophy, progeria, schizophrenia, severe obesity, Tay-Sachs
disease, and Tourette’s syndrome. And the list goes on and on.
The average human carries from 250 to 300 defective copies of genes and 75 of these variants are associated
with disease.
Many factors can impinge on the DNA present in the nucleus of human cells, e.g., ultraviolet light, ionizing
radiation, and reactions with teratogenic22 chemicals are just a few. The developing fetus is partially protected by the
placenta. This provides a barrier to most molecules of weight in excess of 1000 Daltons. Unfortunately, there are
very many lower molecular weight chemicals and drugs from which there is no protection, most notably alcohol.
The Food and Drug Administration, FDA, has categorized many drugs by their possible effects on a developing
fetus as follows:
17
Yes, men do get breast cancer. In the US that rate is 0.01, while in Turkey, it is much higher.
This disease begins in early childhood when the retina begins to deteriorate, usually leading to blindness.
19
A bone disease characterized by malformed bone matrix with normal calcification. There is a tendency to frequent bone
fractures with normal healing. In some cases, this tendency of the bone to fracture decreases and may disappear completely.
20
This disorder affects cell growth of neural (nerve and brain) tissue.
21
Cancer cells have an impaired programmed cell death function, so they grow unabated—as if they are immortal.
22
The word means causing embryonic or fetal mutation.
18
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A.
B.
C.
D.
X.
Controlled Studies Show No Risk. Adequate, well-controlled studies in pregnant
women have failed to demonstrate a risk to the fetus in any trimester of pregnancy.
No Evidence of Risk in Humans. Adequate, well-controlled studies in pregnant
women have not shown increased risk of fetal abnormalities despite adverse findings
in animals, or, in the absence of adequate human studies, animal studies show no fetal
risk. The chance of fetal harm is remote, but remains a possibility.
Risk Cannot Be Ruled Out. Adequate, well-controlled human studies are lacking,
and animal studies have shown a risk to the fetus or are lacking as well. There is a
chance of fetal harm if the drug is administered during pregnancy; but the potential
benefits may outweigh the potential risk.
Positive Evidence of Risk. Studies in humans, or investigational or post-marketing
data, have demonstrated fetal risk. Nevertheless, potential benefits from the use of the
drug may outweigh the potential risk. For example, the drug may be acceptable if
needed in a life-threatening situation or serious disease for which safer drugs cannot
be used or are ineffective.
Contraindicated in Pregnancy. Studies in animals or humans, or investigational or
post-marketing reports, have demonstrated positive evidence of fetal abnormalities or
risk which clearly outweighs any possible benefit to the patient.
Some examples of common drugs that pose a high risk, as categorized above, include:
• D: lithium (antidepressant), paclitaxel (anticancer), phenobarbital (anticonvulsant);
• X: lovastatin (widely used for lowering blood cholesterol), accutane & tazarotene (widely used in treating
severe acne and psoriasis), and warfarin (one of the most commonly used blood thinners).
Surprisingly, not all FDA approved drugs have been assigned a pregnancy effect category!
References
Klug & Cummings – Essentials of Genetics, 5th edition
Perta & Salzberg – Genome Biology (2010)
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