ANATOMY AND PHYSIOLOGY
GENETICS AND CELLULAR FUNCTIONS
LEARN THROUGH YOUR COURSE AND FORTIFY ALL YOUR WEAKNESS WITH MEDICAL KNOWLEDGE
The Nucleic Acids 130
• Organization of the Chromatin 130
• DNA Structure and Function 130
• RNA Structure and Function 133
Protein Synthesis and Secretion 134
• Preview 134
• The Genetic Code 134
• Transcription 136
• Translation 136
• Chaperones and Protein Structure 137
• Posttranslational Modification 138
• Packaging and Secretion 139
DNA Replication and the Cell Cycle 139
• DNA Replication 139
• Errors and Mutations 142
• The Cell Cycle 142
• Mitosis 143
• Timing of Cell Division 145
Chromosomes and Heredity 145
• The Karyotype 146
• Genes and Alleles 147
• Multiple Alleles, Codominance, and
Incomplete Dominance 148
• Polygenic Inheritance and Pleiotropy 148
• Sex Linkage 149
• Penetrance and Environmental Effects 149
• Dominant and Recessive Alleles at the
Population Level 149
Chapter Review 152
INSIGHTS
4.1 Medical History: Miescher and the
Discovery of DNA 130
4.2 Medical History: Discovery of the
Double Helix 132
4.3 Clinical Application: Can We
Replace Brain Cells? 143
4.4 Clinical Application: Cancer 151
Some of the basic ideas of heredity have been known since
antiquity, but a scientific understanding of how traits are
passed from parent to offspring began with the Austrian monk
Gregor Mendel (1822–84) and his famous experiments on garden
peas. In the early twentieth century, the importance of Mendel’s
work was realized and chromosomes were first seen with the
microscope. Cytogenetics now uses techniques of cytology and
microscopy to study chromosomes and their relationship to hereditary traits. Molecular genetics uses the techniques of biochemistry to study the structure and function of DNA. In this chapter,
we bring together some of the findings of molecular genetics,
cytogenetics, and mendelian heredity to explore what the genes
are, how they regulate cellular function, and how they are passed
on when cells divide and people reproduce. A few basic concepts
of heredity are introduced as a foundation for understanding concepts ranging from color blindness to blood types in the chapters
that follow.
The Nucleic Acids
Objectives
When you have completed this section, you should be able to
• describe how DNA is organized in the nucleus; and
• compare the structures and functions of DNA and RNA.
With improvements in the microscope, nineteenth-century
cytologists saw that the nucleus divides in preparation for
cell division, and they came to regard the nucleus as the
most likely center of heredity. This led to a search for the
biochemical keys to heredity in the nucleus, and thus to
the discovery of deoxyribonucleic acid (DNA) (insight 4.1).
DNA directly or indirectly regulates all cellular form and
function.
Insight 4.1 Medical History
Miescher and the Discovery of DNA
Swiss biochemist Johann Friedrich Miescher (1844–95) was one of
the first scientists intent on identifying the hereditary material in
nuclei. In order to isolate nuclei with minimal contamination,
Miescher chose to work with cells that have large nuclei and very little cytoplasm. At first he chose white blood cells extracted from the
pus in used bandages from a hospital; later, he used the sperm of
salmon—probably more agreeable to work with than used bandages!
Miescher isolated an acidic substance rich in phosphorus, which he
named nuclein. His student, Richard Altmann, later called it nucleic
acid—a term we now use for both DNA and RNA. Miescher correctly
guessed that “nuclein” (DNA) was the hereditary matter of the cell,
but he was unable to provide strong evidence for this conjecture,
and his work was harshly criticized. He died of tuberculosis at the
age of 51.
Organization of the Chromatin
A human cell usually has 46 molecules of DNA with an
average length of 44 mm (total slightly over 2 m). Each
molecule is 2 nm in diameter. To put this in perspective,
if a DNA molecule were the thickness of a telephone pole
(20 cm, or 8 in.), it would reach about 4,400 km (2,700 mi)
into space—far higher than the orbits of satellites and
space shuttles. Imagine trying to make a pole 20 cm thick
and 4,400 km long without breaking it! The problem for a
cell is even greater. It has 46 DNA molecules packed
together in a single nucleus, and it has to make an exact
copy of every one of them and distribute these equally to
its two daughter cells when the cell divides. Keeping the
DNA organized and intact is a tremendous feat.
Molecular biology and high-resolution electron
microscopy have provided some insight into how this task
is accomplished. Chromatin looks like a granular thread
(fig. 4.1a). The granules, called nucleosomes, consist of a
cluster of eight proteins called histones, with the DNA
molecule wound around the cluster. Histones serve as
spools that protect and organize the DNA. Other nuclear
proteins called nonhistones seem to provide structural
support for the chromatin and regulate gene activity.
Winding DNA around the nucleosomes makes the
chromatin shorter and more compact, but chromatin also
has higher orders of structure. The “granular thread,” about
10 nm wide, further twists into a coil about 30 nm wide.
When a cell prepares to undergo division, the chromatin
further supercoils into a fiber about 200 nm wide (fig. 4.1b).
Thus, the 2 m of DNA in each cell becomes shortened and
compacted in an orderly way that prevents tangling and
breakage without interfering with genetic function.
DNA Structure and Function
Nucleic acids are polymers of nucleotides (NEW-clee-ohtides). A nucleotide consists of a sugar, a phosphate group,
and a single- or double-ringed nitrogenous (ny-TRODJ-ehnus) base. Three bases—cytosine (C), thymine (T), and
uracil (U)—have a single carbon-nitrogen ring and are classified as pyrimidines (py-RIM-ih-deens). The other two
bases—adenine (A) and guanine (G)—have double rings
and are classified as purines (fig. 4.2). The bases of DNA are
C, T, A, and G, whereas the bases of RNA are C, U, A, and G.
The structure of DNA resembles a ladder (fig. 4.3a).
Each sidepiece is a backbone composed of phosphate
groups alternating with the sugar deoxyribose. The steplike connections between the backbones are pairs of
nitrogenous bases. Imagine this as a soft rubber ladder that
you can twist, so that the two backbones become entwined
to resemble a spiral staircase. This is analogous to the
shape of the DNA molecule, described as a double helix.
The nitrogenous bases face the inside of the helix and
hold the two backbones together with hydrogen bonds.
Across from a purine on one backbone, there is a pyrimidine
on the other. A given purine cannot arbitrarily bind to just
any pyrimidine. Adenine and thymine form two hydrogen
bonds with each other, and guanine and cytosine form three,
as shown in figure 4.3b. Therefore, wherever there is an A
on one backbone, there is a T across from it, and every C is
paired with a G. A–T and C–G are called the base pairs. The
fact that one strand governs the base sequence of the other is
called the law of complementary base pairing. It enables us
to predict the base sequence of one strand if we know the
sequence of the complementary strand. The pairing of each
small, single-ringed pyrimidine with a large, double-ringed
purine gives the DNA molecule its uniform 2-nm width.
Think About It
What would be the base sequence of the DNA strand
across from ATTGACTCG? If a DNA molecule were
known to be 20% adenine, predict its percentage of
cytosine and explain your answer.
Medical History
Discovery of the Double Helix
The components of DNA were known by 1900—the sugar, phosphate,
and bases—but the technology did not exist then to determine how
they were put together. The credit for that discovery went mainly to
James Watson and Francis Crick in 1953 (fig. 4.4). The events surrounding their discovery of the double helix represent one of the most
dramatic stories of modern science—the subject of many books and a
movie. When Watson and Crick came to share a laboratory at Cambridge University in 1951, both had barely begun their careers. Watson,
age 23, had just completed his Ph.D. in the United States, and Crick, 11
years older, was a doctoral candidate. Yet the two were about to
become the most famous molecular biologists of the twentieth century, and the discovery that won them such acclaim came without a
single laboratory experiment of their own.
Others were fervently at work on DNA, including Rosalind
Franklin and Maurice Wilkins at King’s College in London. Using a
technique called X-ray diffraction, Franklin had determined that
DNA had a repetitious helical structure with sugar and phosphate on
the outside of the helix. Without her permission, Wilkins showed one
of Franklin’s best X-ray photographs to Watson. Watson said, “The
instant I saw the picture my mouth fell open and my pulse began to
race.” It provided a flash of insight that allowed the Watson and
Crick team to beat Franklin to the goal. They were quickly able to
piece together a scale model from cardboard and sheet metal that
fully accounted for the known geometry of DNA. They rushed a
paper into print in 1953 describing the double helix, barely mentioning the importance of Franklin’s two years of painstaking X-ray
diffraction work in unlocking the mystery of life’s most important
molecule.
For this discovery, Watson, Crick, and Wilkins shared the Nobel Prize
in 1962. Nobel Prizes are awarded only to the living, and in the final
irony of her career, Rosalind Franklin had died in 1958, at the age of
37, of a cancer possibly induced by the X rays that were her window on
DNA architecture.The essential function of DNA is to serve as a code
for the structure of polypeptides synthesized by a cell. A
gene is a DNA nucleotide sequence that codes for one
polypeptide. The next section of this chapter explains in
detail how the genes direct polypeptide synthesis. All the
genes of one person are called the genome (JEE-nome);
geneticists estimate that a human has about 35,000 genes.
These account for only 3% of our DNA; the other 97%
does not code for anything. Some of the noncoding DNA
serves important organizing roles in the chromatin, and
some of it is useless “junk DNA” that has accumulated
over the course of human evolution. The latest triumph of
molecular genetics is the human genome project, an enormous multinational effort that led to the mapping of the
base sequence of the entire human genome. Its completion
(in all but some fine details) in June 2000 was hailed as a
scientific achievement comparable to putting the first man
on the moon.
RNA Structure and Function
DNA directs the synthesis of proteins by means of its
smaller cousins, the ribonucleic acids (RNAs). There are
three types of RNA: messenger RNA (mRNA), ribosomal
RNA (rRNA), and transfer RNA (tRNA). Their individual
roles are described shortly. For now we consider what
they have in common and how they differ from DNA
(table 4.1). The most significant difference is that RNA
is much smaller, ranging from about 70 to 90 bases in
tRNA to slightly over 10,000 bases in the largest mRNA.
DNA, by contrast, may be over a billion base pairs long.
Also, while DNA is a double helix, RNA consists of only
one nucleotide chain, not held together by complementary base pairs except in certain regions of tRNA where
the molecule folds back on itself. The sugar in RNA is
ribose instead of deoxyribose, and one of the pyrimidines of DNA, thymine, is replaced by uracil (U) in
RNA (see fig. 4.2).
The essential function of RNA is to interpret the
code in DNA and direct the synthesis of proteins. RNA
works mainly in the cytoplasm, while DNA remains
safely behind in the nucleus, “giving orders” from there.
This process is described in the next section of this
chapter.
Protein Synthesis and Secretion
Objectives
When you have completed this section, you should be able to
• define genetic code and describe how DNA codes for protein
structure;
• describe the process of assembling amino acids to form a
protein;
• explain what happens to a protein after its amino acid
sequence has been synthesized;
• explain how DNA indirectly regulates the synthesis of
nonprotein molecules.
Everything a cell does ultimately results from the action of
its proteins; DNA directs the synthesis of those proteins.
Cells, of course, synthesize many other substances as
well—glycogen, fat, phospholipids, steroids, pigments,
and so on. There are no genes for these cell products, but
their synthesis depends on enzymes that are coded for by
the genes. For example, even though a cell of the testis has
no genes for testosterone, testosterone synthesis is indirectly under genetic control (fig. 4.5). Since testosterone
strongly influences such behaviors as aggression and sexual drive (in both sexes), we can see that genes also make
a significant contribution to behavior. In this section, we
examine how protein synthesis results from the instructions given in the genes.
Preview
Before studying the details of protein synthesis, it will
be helpful to consider the big picture. In brief, DNA contains a genetic code that specifies which proteins a cell
can make. All the body’s cells except the sex cells contain identical genes, but different genes are activated in
different cells; for example, the genes for digestive
enzymes are active in stomach cells but not in muscle
cells. When a gene is activated, a molecule of messenger
RNA (mRNA), a sort of mirror-image copy of the gene, is
made. Most mRNA migrates from the nucleus to the
cytoplasm, where its code is “read” by a ribosome. Ribosomes are composed of ribosomal RNA (rRNA) and
enzymes. Transfer RNA (tRNA) delivers amino acids to
the ribosome, and the ribosome chooses from among
these to assemble amino acids in the order directed by
the mRNA.
In summary, you can think of the process of protein
synthesis as DNA→mRNA→protein, with each arrow
reading as “codes for the production of.” The step from
DNA to mRNA is called transcription, and the step from
mRNA to protein is called translation. Transcription
occurs in the nucleus, where the DNA is, and most translation occurs in the cytoplasm. Recent research has
shown, however, that 10% to 15% of proteins are synthesized in the nucleus, with both steps occurring there.
The Genetic Code
The body makes more than 2 million different proteins,
all from the same 20 amino acids and all encoded by
genes made of just 4 nucleotides (A, T, C, G)—a striking
illustration of how a great variety of complex structures
can be made from a small variety of simpler components. The genetic code is a system that enables these 4
nucleotides to code for the amino acid sequences of all
proteins.
It is not unusual for simple codes to represent complex information. Computers store and transmit complex
information, including pictures and sounds, in a binary
code with only the symbols 1 and 0. It is not surprising,
then, that a mere 20 amino acids can be represented by a
code of 4 nucleotides; all that is required is to combine
these symbols in varied ways. It requires more than 2
nucleotides to code for each amino acid, because A, U, C,
and G can combine in only 16 ways (AA, AU, AC, AG, UA,
UU, etc.). The minimum code to symbolize 20 amino acids
is 3 nucleotides per amino acid, and indeed this is the case
in DNA. A sequence of 3 DNA nucleotides that stands for
1 amino acid is called a base triplet. The “mirror image”sequence in mRNA is called a codon. The genetic code is
expressed in terms of codons.
Table 4.2 shows a few representative triplets and
codons along with the amino acids they represent. You
can see from this listing that two or more codons can represent the same amino acid. The reason for this is easy to
explain mathematically. Four symbols (N) taken three at
a time (x) can be combined in Nx different ways; that is,
there are 43 64 possible codons available to represent
the 20 amino acids. Only 61 of these code for amino
acids. The other 3—UAG, UGA, and UAA—are called
stop codons; they signal “end of message,” like the
period at the end of a sentence. A stop codon enables the
cell’s protein-synthesizing machinery to sense that it has
reached the end of the gene for a particular protein. The
codon AUG plays two roles—it serves as a code for
methionine and as a start codon. This dual function is
explained shortly
Transcription
Most protein synthesis occurs in the cytoplasm, but DNA
is too large to leave the nucleus. It is necessary, therefore,
to make a small RNA copy that can migrate through a
nuclear pore into the cytoplasm. Just as we might transcribe (copy) a document, transcription in genetics means
the process of copying genetic instructions from DNA to
RNA. It is triggered by chemical messengers from the cytoplasm that enter the nucleus and bind to the chromatin at
the site of the relevant gene. An enzyme called RNA polymerase (po-LIM-ur-ase) then binds to the DNA at this
point and begins making RNA. Certain base sequences
(often TATATA or TATAAA) inform the polymerase where
to begin.
RNA polymerase opens up the DNA helix about 17
base pairs at a time. It transcribes the bases from one
strand of the DNA and makes a corresponding RNA.
Where it finds a C on the DNA, it adds a G to the RNA;
where it finds an A, it adds a U; and so forth. The enzyme
then rewinds the DNA helix behind it. Another RNA polymerase may follow closely behind the first one; thus, a
gene may be transcribed by several polymerase molecules
at once, and numerous copies of the same RNA are made.
At the end of the gene is a base sequence that serves as a
terminator, which signals the polymerase to release the
RNA and separate from the DNA.
The RNA produced by transcription is an “immature” form called pre-mRNA. This molecule contains
“sense” portions called exons that will be translated into
a peptide and “nonsense” portions called introns that
must be removed before translation. Enzymes remove the
introns and splice the exons together into a functional
mRNA molecule.
Translation
Just as we might translate a work from Spanish into English, genetic translation converts the language of
nucleotides into the language of amino acids (fig. 4.6).
This job is done by ribosomes, which are found mainly in
the cytosol and on the rough ER and nuclear envelope. A
ribosome consists of two granular subunits, large and
small, each made of several rRNA and enzyme molecules.
The mRNA molecule begins with a leader sequence
of bases that are not translated to protein but serve as a
binding site for the ribosome. The small ribosomal subunit
binds to it, the large subunit joins the complex, and the
ribosome begins pulling the mRNA through it like a ribbon, reading bases as it goes. When it reaches the start
codon, AUG, it begins making protein. Since AUG codes
for methionine, all proteins begin with methionine when
first synthesized, although this may be removed later.
Translation requires the participation of 61 types of
transfer RNA (tRNA), one for each codon (except stop
codons). Transfer RNA is a small RNA molecule that turns
back and coils on itself to form a cloverleaf shape, which
is then twisted into an angular L-shape (fig. 4.7). One end
of the L includes three nucleotides called an anticodon,
and the other end has a binding site specific for one amino
acid. Each tRNA picks up an amino acid from a pool of free
amino acids in the cytosol. One ATP molecule is used to
bind the amino acid to this site and provide the energy that
is used later to join that amino acid to the growing protein.
Thus, protein synthesis consumes one ATP for each peptide bond formed.
When the small ribosomal subunit reads a codon
such as CGC, it must find an activated tRNA with the corresponding anticodon; in this case, GCG. This particular
tRNA would have the amino acid alanine at its other end.
The ribosome binds and holds this tRNA and then reads
the next codon—say GGU. Here, it would bind a tRNA
with anticodon CCA, which carries glycine.
The large ribosomal subunit contains an enzyme that
forms peptide bonds, and now that alanine and glycine are
side by side, it links them together. The first tRNA is no
longer needed, so it is released from the ribosome. The
second tRNA is used, temporarily, to anchor the growing
peptide to the ribosome. Now, the ribosome reads the third
codon—say GUA. It finds the tRNA with the anticodon
CAU, which carries the amino acid valine. The large subunit adds valine to the growing chain, now three amino
acids long. By repetition of this process, the entire protein
is assembled. Eventually, the ribosome reaches a stop
codon and is finished translating this mRNA. The
polypeptide is turned loose, and the ribosome dissociates
into its two subunits.
One ribosome can assemble a protein of 400 amino
acids in about 20 seconds, but it does not work at the
task alone. After the mRNA leader sequence passes
through one ribosome, a neighboring ribosome takes it
up and begins translating the mRNA before the first
ribosome has finished. One mRNA often holds 10 or 20
ribosomes together in a cluster called a polyribosome
(fig. 4.8). Not only is each mRNA translated by all these
ribosomes at once, but a cell may have 300,000 identical
mRNA molecules undergoing simultaneous translation.
Thus, a cell may produce over 150,000 protein molecules per second—a remarkably productive protein factory! As much as 25% of the dry weight of liver cells,
which are highly active in protein synthesis, is composed of ribosomes.
Many proteins, when first synthesized, begin with a
chain of amino acids called the signal peptide. Like a
molecular address label, the signal peptide determines the
protein’s destination—for example, whether it will be sent
to the rough endoplasmic reticulum, a peroxisome, or a
mitochondrion. (Proteins used in the cytosol lack signal
peptides.) Some diseases result from errors in the signal
peptide, causing a protein to be sent to the wrong address,
such as going to a mitochondrion when it should have
gone to a peroxisome, or causing it to be secreted from a
cell when it should have been stored in a lysosome.
Gunter Blöbel of Rockefeller University received the 1999
Nobel Prize for Physiology or Medicine for discovering
signal peptides in the 1970s.
Figure 4.9 summarizes transcription and translation
and shows how a nucleotide sequence translates to a
hypothetical peptide of 6 amino acids. A protein 500
amino acids long would have to be represented, at a minimum, by a sequence of 1,503 nucleotides (3 for each
amino acid, plus a stop codon). The average gene is probably around 1,200 nucleotides long; a few may be 10 times
this long.
Chaperones and Protein Structure
The amino acid sequence of a protein (primary structure)
is only the beginning; the end of translation is not the end
of protein synthesis. The protein now coils or folds into
its secondary and tertiary structures and, in some cases,
associates with other polypeptide chains (quaternary
structure) or conjugates with a nonprotein moiety, such as
a vitamin or carbohydrate. It is essential that these
processes not begin prematurely as the amino acid
sequence is being assembled, since the correct final shape
may depend on amino acids that have not been added yet.
Therefore, as new proteins are assembled by ribosomes,
they are sometimes picked up by older proteins called
chaperones. A chaperone prevents a new protein from
folding prematurely and assists in its proper folding once
the amino acid sequence has been completed. It may also
escort a newly synthesized protein to the correct destination in a cell, such as the plasma membrane, and help to
prevent improper associations between different proteins. As in the colloquial sense of the word, a chaperone
is an older protein that escorts and regulates the behavior
of the “youngsters.” Some chaperones are also called
stress proteins or heat-shock proteins because they are
produced in response to heat or other stress on a cell and
help damaged proteins fold back into their correct functional shapes.
Posttranslational Modification
If a protein is going to be used in the cytosol (for example, the enzymes of glycolysis), it is likely to be made by
free ribosomes in the cytosol. If it is going to be packaged
into a lysosome or secreted from the cell, however, its signal peptide causes the entire polyribosome to migrate to
the rough ER and dock on its surface. Assembly of the
amino acid chain is then completed on the rough ER and
the protein is sent to the Golgi complex for final modification. Thus, we turn to the functions of these organelles
in the modification, packaging, and secretion of a protein. When a protein is produced on the rough ER, its signal
peptide threads itself through a pore in the ER membrane
and drags the rest of the protein into the cisterna. Enzymes
in the cisterna then remove the signal peptide and modify
the new protein in a variety of ways—removing some amino
acids segments, folding the protein and stabilizing it with
disulfide bridges, adding carbohydrate moieties, and so
forth. Such changes are called posttranslational modification. Insulin, for example, is first synthesized as a polypeptide of 86 amino acids. In posttranslational modification, the
chain folds back on itself, three disulfide bridges are formed,
and 35 amino acids are removed. The final insulin molecule
is therefore made of two chains of 21 and 30 amino acids
held together by disulfide bridges (see fig. 17.15).
When the rough ER is finished with a protein, it
pinches off clathrin-coated transport vesicles. Like the
address on a letter, clathrin may direct the vesicle to its
destination, the Golgi complex. The Golgi complex
removes the clathrin, fuses with the vesicle, and takes the
protein into its cisterna. Here, it may further modify the
protein, for example by adding carbohydrate to it. Such
modifications begin in the cisterna closest to the rough ER.
Each cisterna forms transport vesicles that carry the protein to the next cisterna, where different enzymes may further modify the new protein.
Packaging and Secretion
When the protein is processed by the last Golgi cisterna, farthest from the rough ER, that cisterna pinches off membranebounded Golgi vesicles containing the finished product.
Some Golgi vesicles become secretory vesicles, which
migrate to the plasma membrane and release the product by
exocytosis. This is how a cell of the salivary gland, for example, secretes mucus and digestive enzymes. The destinations of these and some other newly synthesized proteins
are summarized in table 4.3.
DNA Replication and the Cell Cycle
ObjectivesWhen you have completed this section, you should be able to
• describe how DNA is replicated;
• discuss the consequences of replication errors;
• describe the life history of a cell, including the events of mitosis; and
• explain how the timing of cell division is regulated.
Before a cell divides, it must duplicate its DNA so it can give a complete copy of the genome to each daughter cell. Since DNA controls all cellular function, this replication process must be very exact. We now examine how it is accomplished and consider the consequences of mistakes.
DNA Replication
The law of complementary base pairing shows that we can predict the base sequence of one DNA strand if we know the sequence of the other. More importantly, it enables a cell to reproduce one strand based on information in the other. This immediately occurred to Watson and Crick when they discovered the structure of DNA. Watson was hesitant to make such a grandiose claim in their first publication, but Crick implored, “Well, we’ve got to say something! Otherwise people will think these two unknown chaps are so dumb they don’t even realize the implications of their own work!” Thus, the last sentence of their first paper modestly stated, “It has not escaped our notice that the specific pairing we have postulated . . . immediately suggests a possible copying mechanism for the genetic material.” Five weeks later they published a second paper pressing this point more vigorously. The basic idea of DNA replication is evident from its base pairing, but the way in which DNA is organized in the chromatin introduces some complications that were not apparent when Watson and Crick first wrote. The fundamental steps of the replication process are as follows:
1. The double helix unwinds from the histones.
2. Like a zipper, an enzyme called DNA helicase
opens up a short segment of the helix, exposing its nitrogenous bases. The point where one strand of DNA is “unzipped” and separates from its complementary strand is called a replication fork
. 3. An enzyme called DNA polymerase moves along the opened strands, reads the exposed bases, and like a matchmaker, arranges “marriages” with complementary free nucleotides in the nucleoplasm. If the polymerase finds the sequence TCG, for example, it assembles AGC across from it. One polymerase molecule moves away from the replication fork replicating one strand of the opened DNA, and another polymerase molecule moves in the opposite direction, replicating the other strand. Thus, from the old DNA molecule, two new ones are made. Each new DNA consists of one new helix synthesized from free nucleotides and one helix conserved from the parent DNA . The process is therefore called semiconservative replication.
4. While DNA is synthesized in the nucleus, new histones are synthesized in the cytoplasm. Millions of histones are transported into the nucleus within a few minutes after DNA replication, and each new DNA helix wraps around them to make new nucleosomes.
Despite the complexity of this process, each DNA polymerase works at an impressive rate of about 100 base pairs per second. Even at this rate, however, it would take weeks for one polymerase molecule to replicate even one chromosome. But in reality, thousands of polymerase molecules work simultaneously on each DNA molecule and all 46 chromosomes are replicated in a mere 6 to 8 hours.
Errors and Mutations
DNA polymerase is fast and accurate, but it makes mistakes. For example, it might read A and place a C across from it where it should have placed a T. In Escherichia coli, a bacterial species in which DNA replication has been most thoroughly studied, about three errors occur for every 100,000 bases copied. At this rate of error, every generation of cells would have about 1,000 faulty proteins, coded for by DNA that had been miscopied. To help prevent such catastrophic damage to the organism, the DNA is continuously scanned for errors. After DNA polymerase has replicated a strand, a smaller polymerase comes along, “proofreads” it, and makes corrections where needed—for example, removing C and replacing it with T. This improves the accuracy of replication to one error per billion bases—only one faulty protein for every 10 cell divisions (in E. coli). Changes in DNA structure, called mutations,1 can result from replication errors or environmental factors. Uncorrected mutations can be passed on to the descendants of that cell, but some of them have no adverse effect. One reason is that a new base sequence sometimes codes for the same thing as the old one. For example, ACC and ACG both code for threonine (see table 4.2), so a mutation from C to G in the third place would not change protein structure. Another reason is that a change in protein structure is not always critical to its function. For example, humans and horses differ in 25 of the 146 amino acids that make up their hemoglobin, yet the hemoglobin is fully functional in both species. Some mutations, however, may kill a cell, turn it cancerous, or cause genetic defects in future generations. When a mutation changes the sixth amino acid of hemoglobin from glutamic acid to valine, for example, the result is a crippling disorder called sickle-cell disease. Clearly some amino acid substitutions are more critical than others, and this affects the severity of a mutation.
The Cell Cycle
Most cells periodically divide into two daughter cells, so a cell has a life cycle extending from one division to the next. This cell cycle (fig. 4.12) is divided into four main phases: G1, S, G2, and M. G1 is the first gap phase, an interval between cell division and DNA replication. During this time, a cell synthesizes proteins, grows, and carries out its preordained tasks for the body. Almost all of the discussion in this book relates to what cells do in the G1 phase. Cells in G1 also begin to replicate their centrioles in preparation for the next cell division and accumulate the materials needed to replicate their DNA in the next phase. In cultured cells called fibroblasts, which divide every 18 to 24 hours, G1 lasts 8 to 10 hours. S is the synthesis phase, in which a cell carries out DNA replication. This produces two identical sets of DNA molecules, which are then available, like the centrioles, to be divided up between daughter cells at the next cell division. This phase takes 6 to 8 hours in cultured fibroblasts. G2, the second gap phase, is a relatively brief interval (4 to 6 hours) between DNA replication and cell division. In G2, a cell finishes replicating its centrioles and synthesizes enzymes that control cell division. M is the mitotic phase, in which a cell replicates its nucleus and then pinches in two to form two new daughter cells. In cultured fibroblasts, the M phase takes 1 to 2 hours. The details of this phase are considered in the next section. Phases G1, S, and G2 are collectively called interphase—the time between M phases. The length of the cell cycle varies greatly from one cell type to another. Stomach and skin cells divide rapidly, bone and cartilage cells slowly, and skeletal muscle cells and nerve cells not at all (see insight 4.3). Some cells leave the cell cycle for a “rest” and cease to divide for days, years, or the rest of one’s life. Such cells are said to be in the G0 (G-zero) phase. The balance between cells that are actively cycling and those standing by in G0 is an important factor in determining the number of cells in the body. An inability to stop cycling and enter G0 is characteristic of cancer cells
Insight 4.3 Clinical Application
Can We Replace Brain Cells?
Until recently, neurons (nerve cells) of the brain were thought to be irreplaceable; when they died, we thought, they were gone forever. We believed, indeed, that there was good reason for this. Motor skills and memories are encoded in intricate neural circuits, and the growth of new neurons might disrupt those circuits. Now we are not so sure. A chemical called BrDU (bromodeoxyuridine) can be used to trace the birth of new cells, because it becomes incorporated into their DNA. BrDU is too toxic to use ordinarily in human research. However, in cancer patients, BrDU is sometimes used to monitor the growth of tumors. Peter Eriksson, at Göteborg University in Sweden, obtained permission from the families of cancer victims to examine the brain tissue of BrDU-treated patients who had died. In the hippocampus, a region of the brain concerned with memory, he and collaborator Fred Gage found as many as 200 new neurons per cubic millimeter of tissue, and estimated that up to 1,000 new neurons may be born per day even in people in their 50s to 70s. These new neurons apparently arise not by mitosis of mature neurons (which are believed to be incapable of mitosis), but from a reserve pool of embryonic stem cells. It remains unknown whether new neurons are produced late in life in other regions of the brain.
Mitosis
Mitosis (my-TOE-sis), in the sense used here, is the process by which a cell divides into two daughter cells with identical copies of its DNA. (Some define it as division of the nucleus only and do not include the subsequent cell division.) Mitosis has four main functions:
1. formation of a multicellular embryo from a fertilized egg;
2. tissue growth
3. replacement of old and dead cells; and
4. repair of injured tissues.
Egg and sperm cells are produced by a combination of mitosis and another form of cell division, meiosis, described in chapter 27. Otherwise, all cells of the body are produced entirely by mitosis. Four phases of mitosis are recognizable—prophase, metaphase, anaphase, and telophase (fig. 4.13). In prophase,2 at the outset of mitosis, the chromosomes supercoil into short, dense rods (fig. 4.14) which are easier to distribute to daughter cells than the long, delicate chromatin. A chromosome at this stage consists of two genetically identical bodies called sister chromatids, joined together at a pinched spot called the centromere. At prophase, there are 46 chromosomes, two chromatids per chromosome, and one molecule of DNA in each chromatid. The nuclear envelope disintegrates during prophase and releases the chromosomes into the cytosol. The centrioles begin to sprout elongated microtubules, which push the centrioles apart as they grow. Eventually, a pair of centrioles lies at each pole of the cell. In metaphase,3 the chromosomes line up at random along the midline of the cell. Microtubules grow toward them from each centriole and some attach to the centromeres. This forms a football-shaped array called the mitotic spindle. Shorter microtubules also radiate from each centriole pair to form a star-shaped array called an aster.4 These microtubules anchor the centrioles to the nearby plasma membrane. In anaphase,5 each centromere divides in two and chromatids separate from each other. Each chromatid is now a chromosome in its own right. These two daughter chromosomes migrate to opposite poles of the cell, with their centromeres leading the way and their arms trailing behind. There is some evidence that the spindle fiber acts a little like a railroad track, and a protein complex in the centromere called the kinetochore6 (kih-NEE-toe-core) acts as a molecular motor that propels the chromosome along the track. One of the kinetochore proteins is dynein, the same motor molecule that causes movement of cilia and flagella (see chapter 3). Since sister chromatids are genetically identical, and since each daughter cell receives one chromatid from each metaphase chromosome, you can see why the daughter cells of mitosis are genetically identical. In telophase,7 the chromosomes cluster on each side of the cell. The rough ER produces a new nuclear envelope around each cluster, and the chromosomes begin to uncoil and return to the thinly dispersed chromatin form. The mitotic spindle breaks up and vanishes. Each new nucleus forms nucleoli, indicating it has already begun making RNA and preparing for protein synthesis. Telophase is the end of nuclear division but overlaps with cytokinesis8 (SY-toe-kih-NEE-sis), division of the cytoplasm. Cytokinesis is achieved by the motor protein myosin pulling on microfilaments of actin in the membrane skeleton. This creates a crease called the cleavage furrow around the equator of the cell, and the cell eventually pinches in two. Interphase has now begun for these new cells.
Timing of Cell Division
One of the most important questions in biology is what signals cells when to divide and when to stop. The activation and inhibition of cell division are subjects of intense research for obvious reasons such as management of cancer and tissue repair. Cells divide when (1) they grow large enough to have enough cytoplasm to distribute to their two daughter cells; (2) they have replicated their DNA, so they can give each daughter cell a duplicate set of genes; (3) they receive an adequate supply of nutrients; (4) they are stimulated by growth factors, chemical signals secreted by blood platelets, kidney cells, and other sources; or (5) neighboring cells die, opening up space in a tissue to be occupied by new cells. Cells stop dividing when nutrients or growth factors are withdrawn or when they snugly contact neighboring cells. The cessation of cell division in response to contact with other cells is called contact inhibition.
Chromosomes and Heredity
Objectives
When you have completed this section, you should be able to
• describe the paired arrangement of chromosomes in the human karyotype;
• define allele and discuss how alleles affect the traits of an individual; and
• discuss the interaction of heredity and environment in producing individual traits.
Heredity is the transmission of genetic characteristics from parent to offspring. Several traits and diseases discussed in the forthcoming chapters are hereditary: baldness, blood types, color blindness, and hemophilia, for example. Thus it is appropriate at this point to lay the groundwork for these discussions by introducing a few basic principles of normal heredity. Hereditary defects are described in chapter 29 along with nonhereditary birth defects.
The Karyotype
A karyotype (fig. 4.15) is a chart of the chromosomes isolated from a cell at metaphase, arranged in order by size and structure. It reveals that most human cells, with the exception of germ cells (described shortly), contain 23 pairs of similar-looking chromosomes (except for X and Y chromosomes). The two chromosomes in each pair are called homologous9 (ho-MOLL-uh-gus) chromosomes. One is inherited from the mother and one from the father. Two chromosomes, designated X and Y, are called sex chromosomes and the other 22 pairs are called autosomes (AW-toe-somes). A female normally has a homologous pair of X chromosomes, whereas a male has one X chromosome and a much smaller Y chromosome The paired state of the homologous chromosomes results from the fact that a sperm cell bearing 23 chromosomes fertilizes an egg, which also has 23. Sperm and egg cells, and the cells on their way to becoming sperm and eggs, are called germ cells. All other cells of the body are called somatic cells. Somatic cells are described as diploid10 because their chromosomes are in homologous pairs, whereas germ cells beyond a certain stage of development are haploid,11 meaning they contain half as many chromosomes as the somatic cells. In meiosis (see chapter 27), homologous chromosomes become segregated from each other into separate daughter cells leading to the haploid sex cells. At fertilization, one set of paternal (sperm) chromosomes unites with one set of maternal (egg) chromosomes, restoring the diploid number to the fertilized egg and the somatic cells that arise from it. Although the two chromosomes of a homologous pair appear to be identical, they come from different parents and therefore are not genetically identical.
Genes and Alleles
Each chromosome carries many genes. The location of a particular gene on a chromosome is called its locus. Homologous chromosomes have the same gene at the same locus, although they may carry different forms of that gene, called alleles12 (ah-LEELS), which produce alternative forms of a particular trait. Frequently, one allele is dominant and the other one recessive. If at least one chromosome carries the dominant allele, the corresponding trait is usually detectable in the individual. A dominant allele masks the effect of any recessive allele that may be present. Recessive alleles are therefore expressed only when present on both of the homologous chromosomes— that is, when the individual has no dominant allele at that locus. Typically, but not always, dominant alleles code for a normal, functional protein and recessive alleles for a nonfunctional variant of the protein. The shape of the outer ear presents an example of dominant and recessive genetic effects. When the ears are developing in a fetus, a “death signal” is often activated in cells that attach the earlobe to the side of the head. These cells die, causing the earlobe to separate from the head. A person will then have “detached earlobes.” This occurs in people who have either one or two copies of a dominant allele which we will denote D. If both homologous chromosomes have the recessive version of this gene, d, the cell suicide program is not activated, and the earlobes remain attached (fig. 4.16a). (It is customary to represent a dominant allele with a capital letter and a recessive allele with its lowercase equivalent.) Individuals with two identical alleles, such as DD or dd, are said to be homozygous13 (HO-mo-ZY-gus) for that trait. If the homologous chromosomes have different alleles for that gene (Dd), the individual is heterozygous14 (HET-eroh-ZY-gus). The alleles that an individual possesses for a particular trait constitute the genotype (JEE-no-type). A detectable trait such as attached or detached earlobes, resulting either from the genotype or from environmental influences, is called the phenotype15 (FEE-no-type). We say that an allele is expressed if it shows in the phenotype of an individual. Earlobe allele d is expressed only when it is present in a homozygous state (dd); allele D is expressed whether it is homozygous (DD) or heterozygous (Dd). The only way most recessive alleles can be expressed is for an individual to inherit them from both parents. Recessive traits can “skip” one or more generations. A diagram called a Punnett square (fig. 4.16b) shows how two heterozygous parents with detached earlobes can produce a child with attached lobes. Across the top are the two genetically possible types of eggs the mother could produce, and on the left side are the possible types of sperm from the father. The four cells of the square show the genotypes and phenotypes that would result from each possible combination of sperm and egg. You can see that three of the possible combinations would produce a child with detached lobes (genotypes DD and Dd), but one combination (dd) would produce a child with attached lobes. Therefore, the attached-lobe trait skipped the parental generation in this case but could be expressed in their child. This phenomenon becomes more significant when parents are heterozygous carriers of hereditary diseases such as cystic fibrosis—individuals who carry a recessive allele and may pass it on, but do not phenotypically express it in themselves. For some hereditary diseases, tests are available to detect carriers and allow couples to weigh their risk of having children with genetic disorders. Genetic counselors perform genetic testing or refer clients for tests, advise couples on the probability of transmitting genetic diseases, and assist people in coping with genetic disease
.
Multiple Alleles, Codominance, and
Incomplete Dominance
.
Some genes exist in more than two allelic forms—that is,
there are multiple alleles within the collective genetic
makeup, or gene pool, of the population as a whole. For
example, there are over 100 alleles responsible for cystic
fibrosis, and there are 3 alleles for ABO blood types. Two
of the ABO blood type alleles are dominant and symbolized with a capital I (for immunoglobulin) and a superscript: I
A and I
B
. There is one recessive allele, symbolized
with a lowercase i. Which two alleles one inherits determines the blood type, as follows
.
.
Genotype Phenotype
IAIA Type A
.
IAi Type A
.
IBIB Type B
.
IBi Type B
.
IAIB Type AB
.
ii Type O
.
Some alleles are equally dominant, or codominant.
When both of them are present, both are phenotypically
expressed. For example, a person who inherits allele I
A
from one parent and I
B from the other has blood type AB.
These alleles code for enzymes that produce the surface
glycoproteins of red blood cells. Type AB means that both
A and B glycoproteins are present, and type O means that
neither of them is present.
Other alleles exhibit incomplete dominance. When
two different alleles are present, the phenotype is intermediate between the traits that each allele would produce alone. Familial hypercholesterolemia, the disease
discussed in insight 3.3 (p. 113), is a good example. Individuals with two abnormal alleles die of heart attacks in
childhood, those with only one abnormal allele typically die as young adults, and those with two normal
alleles have normal life expectancies. Thus, the heterozygous individuals suffer an effect between the two
extremes.
Polygenic Inheritance and
Polygenic (multiple-gene) inheritance (fig. 4.17a) is a
phenomenon in which genes at two or more loci, or even
on different chromosomes, contribute to a single phenotypic trait. Human eye and skin colors are normal polygenic traits, for example. They result from the combined
expression of all the genes for each trait. Several diseases
are also thought to stem from polygenic inheritance,
including some forms of alcoholism, mental illness, cancer, and heart disease.
Pleiotropy (ply-OT-roe-pee) (fig. 4.17b) is a phenomenon in which one gene produces multiple phenotypic effects. Sickle-cell disease, for example, is caused
by a recessive allele that changes one amino acid in hemoglobin. It causes red blood cells (RBCs) to assume
an abnormally elongated, pointed shape when oxygen
levels are low, and it makes them sticky and fragile. As
RBCs rupture, a person becomes anemic and the spleen
becomes enlarged. Because of the deficiency of RBCs, the
blood carries insufficient oxygen to the tissues, resulting
in multiple, far-reaching effects on different parts of the
body (see chapter 18).
Sex Linkage
Sex-linked traits are carried on the X or Y chromosome
and therefore tend to be inherited by one sex more than
the other. Men are more likely than women to have redgreen color blindness or hemophilia, for example,
because the allele for each is recessive and located on the
X chromosome (X-linked). Women have two X chromosomes. If a woman inherits the recessive hemophilia
allele (h) on one of her X chromosomes, there is still a
good chance that her other X chromosome will carry a
dominant allele (H). H codes for normal blood-clotting
proteins, so her blood clots normally. Men, on the other
hand, have only one X chromosome and normally express
any recessive allele found there (fig. 4.18). Ironically,
even though this hemophilia is far more common among
men than women, a man can inherit it only from his
mother. Why? Because only his mother contributes an X
chromosome to him. If he inherits h on his mother’s X
chromosome, he will have hemophilia. He has no “second chance” to inherit a normal allele on a second X chromosome. A woman, however, gets an X chromosome from
both parents. Even if one parent transmits the recessive
allele to her, the chances are high that she will inherit a
normal allele from her other parent. She would have to
have the extraordinarily bad luck to inherit it from both
parents in order for her to have a trait such as hemophilia
or red-green color blindness.
The X chromosome is thought to carry about 260
genes, most of which have nothing to do with determining
an individual’s sex. There are so few functional genes on
the Y chromosome—concerned mainly with development
of the testes—that virtually all sex-linked traits are associated with the X chromosome.
Penetrance and
Environmental Effects
People do not inevitably exhibit the phenotypes that
would be predicted from their genotypes. For example,
there is a dominant allele that causes polydactyly,16 the
presence of extra fingers or toes. We might predict that
since it is dominant, anyone who inherited the allele
would exhibit this trait. Most do, but others known to have
the allele have the normal number of digits. Penetrance is
the percentage of a population with a given genotype that
actually exhibits the predicted phenotype. If 80% of people with the polydactyly allele actually exhibit extra digits, the allele has 80% penetrance.
Another reason the connection between genotype
and phenotype is not inevitable is that environmental factors play an important role in the expression of all genes.
At the very least, all gene expression depends on nutrition
(fig. 4.19). Children born with the hereditary disease
phenylketonuria (FEN-il-KEE-toe-NEW-ree-uh) (PKU), for
example, become retarded if they eat a normal diet. However, if PKU is detected early, a child can be placed on a
diet low in phenylalanine (an amino acid) and achieve
normal mental development.
No gene can produce a phenotypic effect without
nutritional and other environmental input, and no nutrients can produce a body or specific phenotype without
genetic instructions that tell cells what to do with them. Just
as you need both a recipe and ingredients to make a cake, it
takes both heredity and environment to make a phenotype.
Dominant and Recessive Alleles at
the Population Level
It is a common misconception that dominant alleles must
be more common in the gene pool than recessive alleles.
The truth is that dominance and recessiveness have little
to do with how common an allele is. For example, type O
is the most common ABO blood type in North America,
but it is caused by the recessive allele i. Blood type AB,
caused by the two dominant ABO alleles, is the rarest.
Polydactyly, caused by a dominant allele, also is rare in
the population
ncer
Proper tissue development depends on a balance between cell division
and cell death. When cells multiply faster than they die, they sometimes produce abnormal growths called tumors, or neoplasms.17 The
study of tumors is called oncology.18 Benign19 (beh-NINE) tumors are
surrounded by a connective tissue capsule, grow slowly, and do not
spread to other organs. They are still potentially lethal—even slowgrowing tumors can kill by compressing brain tissue, nerves, blood vessels, or airways. The term cancer refers to malignant20 (muh-LIG-nent)
tumors, which are unencapsulated, fast-growing, and spread easily to
other organs by way of the blood or lymph. The word cancer21 dates to
Hippocrates, who compared the distended veins in some breast tumors
to the outstretched legs of a crab. Malignant cells exhibit no contact
inhibition or respect for tissue boundaries; they readily grow into other
tissues and replace healthy cells. About 90% of cancer deaths result
from this spreading, called metastasis22 (meh-TASS-tuh-sis), rather
than from the primary (original) tumor.
Cancer is classified according to the cells or tissues in which the
tumor originates:
Name Origin
Carcinoma Epithelial cells
Melanoma Pigment-producing skin cells (melanocytes)
Sarcoma Bone, other connective tissue, or muscle
Leukemia Blood-forming tissues
Lymphoma Lymph nodes
Causes of Cancer
The World Health Organization estimates that 60% to 70% of cancer
is caused by environmental agents called carcinogens23 (car-SIN-ohjens). These fall into three categories:
1. Chemicals such as cigarette tar, nitrites and other food
preservatives, and numerous industrial chemicals.
2. Radiation such as rays, particles, particles, and ultraviolet
radiation.
3. Viruses such as type 2 herpes simplex (implicated in some cases
of uterine cancer) and hepatitis C (implicated in some liver
cancer).
Carcinogens are mutagens24 (MEW-tuh-jens)—they trigger gene
mutations. We have several defenses against mutagens: (1) scavenger
cells may remove them before they cause genetic damage; (2) peroxisomes neutralize nitrites, free radicals, and other carcinogenic oxidizing agents; and (3) nuclear enzymes detect and repair damaged DNA.
If these mechanisms fail, or if they are overworked by heavy exposure
to mutagens, a cell may die of genetic damage, it may be recognized
and destroyed by the immune system before it can multiply, or it may
multiply and produce a tumor. Even then, tumors may be destroyed by
a substance called tumor necrosis factor (TNF), secreted by
macrophages and certain white blood cells.
Growth Factors and Cancer Genes
Cancer researchers have linked many forms of cancer to abnormal
growth factors or growth factor receptors. Most cells cannot divide
unless a growth factor binds to a receptor on their surface. When a
growth factor binds to its receptor, the receptor activates cell-division
enzymes in the cell. This stimulates a cell to leave the G0 phase,
undergo mitosis, and develop (differentiate) into various kinds of
mature, functional cells.
Two types of genes have been identified as responsible for malignant tumors—oncogenes and tumor suppressor genes. Oncogenes
are mutated, “misbehaving” forms of normal genes called protooncogenes. Healthy proto-oncogenes code for growth-factors or
growth-factor receptors, whereas mutated oncogenes cause malfunctions in the growth-factor mechanism. An oncogene called sis,
for example, causes excessive secretion of growth factors that stimulate blood vessels to grow into a tumor and supply it with the rich
blood supply that it requires. An oncogene known as ras, responsible for about one-quarter of human cancers, codes for abnormal
growth-factor receptors. These receptors act like a switch stuck in
the on position, sending constant cell division signals even when
there is no growth factor bound to them. Many cases of breast and
ovarian cancer are caused by an oncogene called erbB2.
Tumor suppressor (TS) genes inhibit the development of cancer. They
may act by opposing the action of oncogenes, promoting DNA repair, or
controlling the normal histological organization of tissues, which is
notably lacking in malignancies. A TS gene called p16 acts by inhibiting
one of the enzymes that drives the cell cycle. Thus, if oncogenes are like
the “accelerator” of the cell cycle, then TS genes are like the “brake.” Like
other genes, TS genes occur in homologous pairs, and even one normal
TS gene in a pair is sometimes sufficient to suppress cancer. Damage to
both members of a pair, however, removes normal controls over cell
division and tends to trigger cancer. The first TS gene discovered was the
Rb gene, which causes retinoblastoma, an eye cancer of infants.
Retinoblastoma occurs only if both copies of the Rb gene are damaged.
In the case of a TS gene called p53, however, damage to just one copy is enough to trigger cancer. Gene p53 is a large gene vulnerable to many
cancer-causing mutations; it is involved in leukemia and in colon, lung,
breast, liver, brain, and esophageal tumors.
Cancer often occurs only when several mutations have accumulated at different gene sites. Colon cancer, for example, requires
damage to at least three TS genes on chromosomes 5, 17, and 18 and
activation of an oncogene on chromosome 12. It takes time for so
many mutations to accumulate, and this is one reason why colon
cancer afflicts elderly people more than the young. In addition, the
longer we live, the more carcinogens we are exposed to, the less efficient our DNA and tissue repair mechanisms become, and the less
effective our immune system is at recognizing and destroying malignant cells.
The Lethal Effects of Cancer
Cancer is almost always fatal if it is not treated. Malignant tumors can
kill in several ways:
• Cancer displaces normal tissue, so the function of the affected
organ deteriorates. Lung cancer, for example, can destroy so much
tissue that oxygenation of the blood becomes inadequate to
support life. You might think that an increased number of cells in
an organ such as the liver would enable it to function better. In
malignant tumors, however, the cells are in an immature state and
unable to carry out the functions of mature cells of the same
organ. Also, a tumor often consists of cells that have metastasized
from elsewhere and are not typical of the host organ anyway. A colon cancer whose malignant cells have metastasized to the liver,
for example, replaces liver tissue but cannot perform any of the
liver’s essential functions.
• Tumors can invade blood vessels, causing fatal hemorrhages.
• Tumors can block vital passageways. The growth of a tumor can
put pressure on a bronchus of the lung, obstructing air flow and
causing pulmonary collapse, or it can compress a major blood
vessel, reducing the delivery of blood to a vital organ or its return
to the heart.
• Tumors have a high metabolic rate and compete with healthy
tissues for nutrition. Other organs of the body may even break
down their own proteins to nourish the tumor. This leads to
general weakness, fatigue, emaciation, and susceptibility to
infections. Some forms of cancer cause cachexia (ka-KEX-ee-ah),
an extreme wasting away of muscular and adipose tissue that
cannot be corrected with nutritional therapy.
