;'PsO

The National Institute of
General Medical Sciences
(NIGMS) is unique among
the components of the
National Institutes of

Health (NIH) in that its
main mission is the
advancement of the basic
biomedical sciences. It
supports selected research
and research training
programs in areas that
underlie all medical
investigation, such as
cellular and molecular
biology and genetics.
Knowledge resulting from
this work contributes
directly to the progress of
research on specific
diseases in the other
components of NIH.
NIGMS also develops and
supports interdisciplinary
studies in biophysics,
pharmacology, biological
chemistry, physiology, and
developmental biology.
Ylany of the researchers

mentioned in this
brochure worked with
NIGMS support.

INSIDE THE CELL

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

Public Health Service
National Institutes of Health
National Institute of General Medical Sciences
NIH Publication No. 97-1051

Revised June 1997

CONTENTS

3

4 The Fundamental Unit of Life
6 What Are Cells?

14 Biochemistry Adds to the Picture

18 The Astonishing Uniformity of Life

20 The Nucleus, Director of Protein Synthesis

26 The Ribosomes, Protein Factories

28 The Endoplasmic Reticulum, Protein Processor

30 The Golgi Apparatus, Final Protein Sorter

32 Lysosomes and Peroxisomes, the Cell’s “Digestive System”

36 Mitochondria, Energy Converters in the Cell

40 The Cytoskeleton, the Cell’s Physical Props

44 The Surface Membrane, Versatile Gatekeeper

46 Directing Traffic Across the Surface Membrane

48 Signal Transduction, the Job of Receptor Proteins

51 A Look Toward the Future

52 Glossary

THE FUNDAMENTAL UNIT

4

The cell is the fun-
damental unit of
life. Your health
depends on what
happens within
the many different types of
cells that make up your body.
The health of your cells
depends, in turn, on the
function of millions of critical
molecules.

Since the mid- 1940’s,
biomedical researchers have
made enormous progress in
identifying and understanding
these molecules and how they
interact in many cellular
processes. Much of this
research was “basic” — aimed
simply at learning how living
systems work. The fundamental
knowledge developed through
this research can lead to new
ways to diagnose, treat, cure,
or prevent disease.

A stunning example of how
basic cell biology research is
moving toward practical
application is found in studies
of the cycle of cell growth and
division. In recent years,
many details of the biochemical
mechanisms involved in the
normal cell cycle have been

discovered. Scientists have
found the cell cycle to be
regulated by highly complex
interactions between pairs of
proteins that belong to two
general families. Work is
proceeding at top speed to
determine all of the many
molecular interactions and the
order in which they occur
during the cell cycle. This work
is yielding an understanding
of the normal processes of
growth and development that
will, in turn, aid researchers
seeking to treat diseases in
which these processes go awry.

Other scientists are discovering
direct connections between
cell cycle regulation and cancer.
This research is beginning to
demonstrate the specific role
of oncogenes, genes that are
directly involved in the devel-
opment of cancer, and tumor
suppressor genes, which are
involved in cancer when their
normal inhibitory functions
are disrupted.

To help readers understand
some of the exciting biomedical
research being conducted

OF LIFE

today. Inside the Cell provides
an overview of the basic facts
of cell biology. The brochure
also contains some history of
key scientific discoveries.

Many scientists agree that the
history of modern cell biology
began with a convergence of
improved techniques in
microscopy and biochemistry.
In the 1950 ’s, as scientists
working in these fields began
to collaborate, they started to
develop our current picture
of the cell as a complex and
highly organized entity.

They found that a typical cell
is like a miniature body
containing tiny “organs,”
called organelles. One organelle
is the command center, others
provide the cell with energy,
while still others manufacture
proteins and additional
molecules that the cell needs
to survive and to communicate
with the world around it. The
entire cell is enclosed in a fine

“skin,” its surface membrane.
This membrane not only keeps
the cell intact, it also provides
channels that open and close
to allow selected molecules
into and out of the cell.

Scientists are seeking to learn
more about the ways cells
respond to outside signals,
which are often conveyed when
molecules bind to special
receptors in cell membranes.
Because the shape of a mole-
cule plays a large part in
determining its function,
scientists are also keenly
interested in determining the
shape of important molecules

and the rules that cause a
string of chemicals to fold into
a specific molecular shape.

To understand cellular function,
most scientists study parts of
specific biochemical pathways,
such as the cell cycle, that
involve individual molecules,
cells, groups of cells, and
whole organisms. The goal is,
of course, to be able to put
all the parts together to
understand normal cellular
activities and how they
malfunction in disease.

Nuclear membrane

Rough

endoplasmic

reticulum

Ribosomes

Cytoplasm

Centrioles
Golgi apparatus

Cell membrane

Nuclear pore

Rough
endoplasmic
reticulum

Smooth

endoplasmic

reticulum

Peroxisome

Nucleolus

Nucleus

Mitochondrion

Secretory vesicle

Lysosome

This drawing of an idealized
animal cell is based on
photographs taken with
powerful electron microscopes.
Within the cell’s membrane
are such organelles as the
mitochondria (energy
producers), the rough
endoplasmic reticulum
(a site of protein production),
the Golgi apparatus
(a protein sorter), and the
largest organelle, the
nucleus (which contains the
hereditary material DNA). In
addition to these organelles,
cells also contain an
elaborate network of protein
filaments called the
cytoskeleton (not shown here)
that anchor the organelles ,
maintain the cell’s shape, and
direct intracellular traffic.

Free ribosomes

WHAT ARE CELLS?

6

n 1665, the English
physicist Robert Hooke
looked at a sliver of
cork through a micro-
scope lens and noticed
some pores or cells m it.
Hooke believed the cells had
served as containers for the
“noble juices” or “fibrous
threads” of the once-living
cork tree. He thought these
cells existed only in plants,
since he and his scientific
contemporaries had observed
the structures only in plant
material.

Nearly two centuries later,
scientists began to develop
the idea that every living
thing is made up of cells. In
1838, during a now-famous
dinner conversation, two
German scientists — the
botanist Matthias
Schleiden, who had
been studying plant
cells, and the
zoologist Theodor
Schwann, who had
been examining the
nervous tissue

of animals — realized that the
similarities between the
structures they had been
investigating were too strong
to be accidental. In 1847,
Schwann wrote a paper
describing how all animal tissue,
including bone, blood, skin,
muscle, and glands, is com-
posed of cells. Even sperm
and eggs are cells. Schleiden
elaborated on this idea as it
applied to plants. A German
pathologist, Rudolph Virchow,
is given credit for being the
first to state, in 1858, what
became known as the cell
theory: “Every animal appears
as a sum of vital units, each

of which bears in itself the
complete characteristics of life.”

The cell theory united plant
and animal sciences by recog-
nizing that the cell is the
fundamental component of all
living organisms, from orchids
and earthworms to human
beings. It provided an intel-
lectual framework that revealed
the hidden similarities of form
and function in extremely
diverse organisms, and it gave
scientists a way of making
sense out of the bewildering
array of living creatures. But
what is a cell?

Obviously, there are major
differences among cell types.
Muscle cells, which can
contract, have to be quite
different from liver or bone
cells. Nerve cells have
long, thin fibers that, in
humans, may extend
more than 3 feet from
the spinal cord to the
toes, while blood cells
have no projecting

This dra wing of cork tissue, as seen
under a simple microscope, appeared
in Robert llooke's l(>(>7 book.
Microscopy. Ilooke named the
compartments “cells. ”

7

fibers at all. Plant cells have a
unique ability to use light as a
source of energy.

Then what do all these cells
have in common? Discovering
their shared properties was
difficult. At first, scientists
thought that the cell was just a
blob of jelly, or some primordial
soup enclosed in a bag. They
named the jelly “protoplasm.”
For a long time they could not
find anything in the protoplasm,
which is now known as the
“cytoplasm.”

Part of the difficulty in
studying cells, of course, is
due to their extremely small
size. The cells of multicellular
organisms are impossible to
see with the unaided eye.
Schleiden and Schwann, like
cell biologists before and
after, relied upon microscopes
to enlarge the image of cells
so that they could be studied.
Microscopes employ one or

more curved lenses and a
source of illumination
(typically white light) to
magnify cells.

One of the most remarkable
early microscopists was a
Dutch draper named Anton
van Leeuwenhoek, who
ground his own lenses as a
hobby. Van Leeuwenhoek,
who once made a lens from a
grain of sand, used simple
(single-lensed) microscopes to
examine everything from pond
water to the scum on his teeth.

In 1702, van Leeuwenhoek
reported to the Royal
(Scientific) Society of London
that he had observed “a little
clear sort of light in the
middle” of a fish blood cell

cells whose structures
vary according to the

nerve cells , for e

from spine to toe. The
orderly structure of
typical skeletal muscle is
shown here in such

muscle cell were drawn

scale as the

Hair cell

Muscle cell

Rod cell in eye

Anton van Leeuwenhoek
(1632-1723) was an early
niicroscopist who ground
his own lenses as a hobby
and was the first to
observe such living cells
as sperm and pond ivater
microorganisms .

he had been examining. This
description of what was later
called the cell’s nucleus was
the first suggestion that ani-
mal cells had an internal
structure. Throughout the
18th and 19th centuries,
improvements in microscopes
and techniques for selectively
staining cell parts enabled cell
biologists to distinguish other
particles within the cell.
However, researchers could
not study these minute flecks
in detail because they met an

insurmountable obstacle: the
wavelength of light.

A light microscope — even one
with perfect lenses and perfect
illumination — simply cannot
be used to distinguish objects
that are smaller than half the
wavelength of light. White
light has an average wave-
length of 0.55 micrometers,
half of which is 0.275 micro-
meters. (One micrometer is a
thousandth of a millimeter,
and there are about 25,000
micrometers to an inch.
Micrometers are also called
microns.) Any two lines that
are closer together than 0.275
micrometers will be seen as a
single line, and any object
with a diameter smaller than
0.275 micrometers will be
invisible — or, at best, show
up as a blur.

Although the nucleus of a typ-
ical human cell is relatively
large (about 7 micrometers in
diameter), most organelles
vary from a width of only 1
micrometer to structures so fine
that they must be measured in
nanometers (which are 1,000
times smaller than micro-
meters), or even in angstrom
units (10 times smaller than
nanometers). To see such tiny
particles under a microscope,
scientists must bypass light
altogether and use a different
sort of “illumination,” one
with a shorter wavelength.

The invention of the electron
microscope in the 1930’s filled
the bill. In this kind of micro-
scope, electrons are speeded
up in a vacuum until their
wavelength is extremely
short — only one hundred-
thousandth that of white fight.
Beams of these fast-moving
electrons are focused on a cell
sample and are absorbed or

scattered by the cell’s parts so
as to form an image on an
electron-sensitive photographic
plate.

If pushed to the limit, electron
microscopes can make it
possible to view objects as
small as the diameter of an
atom. Most electron micro-
scopes used to study biological
material can “see” down to
about 10 angstroms — an
incredible feat, for although
this does not make atoms
visible, it does allow researchers
to distinguish individual
molecules of biological
importance. In effect, it can
magnify objects up to 1
million times. Nevertheless,
all electron microscopes suffer
from a serious drawback.
Since no living specimen can

9

This is the actual size
of a typical microscope
built by van Leeuwenhoek.
He peered through the
tiny lens opening on one
side of a metal plate
(left) to see the specimen
mounted on the point of
a pin on the other side
(right). The specimen
could be moved into focus
by a system of screws.

10

survive under their high
vacuum, they cannot show
the ever-changing movements
that characterize a living cell.

The first electron microscopes
were used to study crystals
and were impractical for the
study of cell structure. Cell
researchers had to learn how
to cut extremely thin slices of
cells, sometimes down to a
thickness of only a few hundred
angstroms, so that electrons
could pass through them. Also,
to ensure contrast between
different parts of the other-
wise transparent cell, new
staining techniques had to be
devised. These techniques use
special metal-containing

The size of common objects
as viewed under
microscopes.

Actual size

Hen egg
Hummingbird egg

Magnified 100 times

Human egg

Human egg
superimposed
on amoeba

• Human liver cell

• Influenza bacillus

Magnified 10,000 times

Pneumococcus bacterium

Hemoglobin molecule

compounds that are absorbed
to differing extents by various
cell parts. The cell sections
also had to be “fixed” in new
ways, to preserve them, and
had to be embedded in new
kinds of materials (mostly
transparent plastic).
Altogether, it was not until
the early 1950’s that electron
microscopes began to be used
routinely for cell biological
studies. While microscopists
were looking through their
instruments at smaller and
smaller particles in cells and
attempting to understand
their structure, another group
of scientists was pursuing an
entirely different, but equally
important, line of research —
biochemistry.

Unit

Equal to

Used to Measure

Centimeter

1/100 meter

Objects visible to the eye

Millimeter

1/10 centimeter

Very large cells

Micrometer (micron)

1/1000 millimeter

Most cells, large organelles

Nanometer

1/1000 micrometer

Small organelles, large molecules

Angstrom

1/10 nanometer

Molecules, atoms

12

Modern Light
Microscopy Gives a
Clear \iew of Cell
Structure and
Movement

Using a microscope the
size of his palm, Anton
van Leeuwenhoek was
ahle to study the move-
ments of one-celled
organisms. Modern
descendants of van
Leeuwenhoek’s light
microscope can he over 6
feet tall, but they con-
tinue to be indispensable
to cell biologists because,
unlike electron micro-
scopes, light microscopes
enable the user to see
living cells in action. The
primary challenge for
light microscopists since
van Leeuwenhoek’s time
has been to enhance the
contrast between pale
cells and their paler
surroundings so that cell
structures and movement
can be seen more easily.
To do this they have
devised ingenious strate-
gies involving video
cameras, polarized light,
digitizing computers.

and other techniques
that are yielding vast
improvements in contrast,
fueling a renaissance in
light microscopy.

A polarizer causes light
waves to move in parallel
planes, thus reducing the
distortion that results
when light scatters across
a magnified object. This
technique was first used
in the 1950’s, and it
provided many new clues
to cellular activities,
particularly the intrica-
cies of cell division.
Further enhancements in
visualizing the cell’s
interior came in the early
1980’s, when microscopists
Shinya Inoue of the
Marine Biological
Laboratory in Woods
Hole, Massachusetts,

and the late Robert Allen
of Dartmouth College
began using video cameras
to study living cells.
Unlike the eye, a video
camera can enhance an
image to “see’' objects
clearly even when the
contrast between subject
and background is very
poor. Inoue and Allen
used video cameras to
watch food-containing
sacs and other structures
in the cell move rapidly
along slender, track-like
organelles. Video images
can now be further
enhanced by digitizing

computers, which, when
attached to a video
camera, scan the cell,
break down the image
into light and dark bits,
and then reconstruct the
image so that “visual
noise” (grayness) is sub-
tracted, while objects of
interest are highlighted.

Another type of micro-
scope, called the confocal
microscope, is having a
great impact on the
study of cell structure. A
confocal microscope
passes a beam of light
over a tiny portion of a
cell, then focuses the
light that reflects off the
specimen through a pin-
hole. A sharply focused,
three-dimensional image
of a cell or cell structure
can be built up by
recording the intensity of

the light beam coming
off each scanned point
and then reconstructing
the whole image on a
viewing screen. Because
confocal microscopes can
be used on living cells,
they allow researchers to
watch cell movements
and the interactions of
neighboring cells.

BIOCHEMISTRY ADDS TO THE

14

The study of bio-
chemistry goes
back to Antoine
Lavoisier, the
18th-century

French scientist who explained
the role of oxygen in the
metabolism of food to provide
energy in both plants and
animals, established the com-
position of water and other
compounds, and introduced
methods of measuring aspects
of chemical reactions, thereby
laying the foundation for
modern chemistry.

In the 19th century, bio-
chemists isolated and
identified many cellular
chemicals — for example,
hemoglobin, the red pigment
in blood, and chlorophyll, the
green pigment in plants. They
discovered that compounds
taken from animal tissue
consisted of many of the same
chemical elements as nonliv-
ing materials. They
isolated the nucleic acids
DNA and RNA, which are
now known to govern heredity
and protein synthesis. They

began to study proteins, espe-
cially enzymes, which catalyze
chemical reactions in cells.

When dealing with cells, the
biochemists behaved quite
unlike the microscopists, who
had enormous respect for the
details of the cell s structure.
The biochemists simply
ground up, or homogenized,
large quantities of cells to
release their contents into a
solution and then analyzed
the mixture (called the
homogenate). Often, the
homogenate was fractionated,
or separated, into individual
components. Usually this was
done with a centrifuge, a
machine that separates parti-
cles according to their size
and density by whirling them

PICTURE

around at high speeds. The
largest and heaviest particles
move to the bottom of the
container most rapidly, fol-
lowed by somewhat smaller
and lighter components, until
after a time there remain only
the smallest and lightest
particles at the top.

In 1925, a Swede, Theodor
Svedberg, developed an
instrument that would prove
at least as revolutionary as
the electron microscope: the
ultracentrifuge, a machine
that could spin its samples at
such high speeds and with
such force (it could attain
hundreds of thousands of
times the force of gravity)
that many of the smaller and
lighter components of the cell
and even proteins and nucleic
acids could be collected
separately and studied for the
first time.

The significance of this new
instrument did not become
apparent until years later.

For several decades, quite a
few biochemists studied the
chemical reactions of the cell
without realizing that the
microscopists could actually
see many of the particles they
were analyzing. Finally, in the
1950’s, the two groups began
to edge closer together. By that
time, electron-microscopic
techniques had been refined.
As the microscopists and
biochemists began to

communicate, there was an
avalanche of discoveries
about the world within the
cells of animals and plants. A
whole new vocabulary had to
be developed for the cellular
structures that the electron
microscope and ultracentrifuge
revealed. Cell biologists
began to define many of the
general characteristics that
cells share, and to discern the
mechanisms that cells use to
make proteins and other vital
molecules. Understanding
these mechanisms, in turn,
enabled them to begin to
identify specific steps in
critical biochemical pathways.
Some of these pathways will
be mentioned in the following
sections on specific cellular
organelles.

Ho w a centrifuge is used
to isolate cell components.
To separate the various
particles in cells, bio-
chemists begin by placing
whole cells in a solution
and then breaking the
cells with a pestle or
with high-frequency
sound waves (a).

The mixture is then
filtered to remove
unbroken cells. At this
point, the cell organelles
and fragments are
free-floating (b).

As the sample is spun in
the centrifuge at increas-
ingly higher speeds and
force, the organelles
begin to settle to the
bottom depending on
their size and density.
First to settle, out are
pellets of nuclei (c).

a.

b.

d.

Crush and fdter Spin at low speed Spin at higher
and force speed and force

Pestle

Whole cell

Spin at highest
speed and force

O’

o%

# A A.

Pellets
of nuclei

O'-

i-q

O.-:

Lysosome

Mitochondrion

At forces greater than

10.000 times that of
gravity, pellets of
mitochondria and
lysosomes sink to the
bottom (d).

Finally , at very high
speeds and at forces

100.000 times that of
gravity, the very lightest
particles and organelles
begin to settle out (e).

Fragments of
endoplasmic
reticulum and
other light
particles

Obtaining Molecules
for Study

To a large extent, the
progress made since the
1950’s in all areas of
biology has been depen-
dent on the development
of techniques to obtain,
grow, and purify suffi-
cient quantities of specific
types of cells and mole-
cules, as well as to
separate cellular compo-
nents in centrifuges. In
the late 1960’s,
scientists devised reliable
methods of growing cells
in the laboratory.
Eventually, they also
learned how to grow cells
in various chemically

defined solutions. These
advances allowed
researchers to study and
compare biochemical
processes in different
types of cells and to
determine the molecular
details of many complex
cellular activities.

Major improvements have
also been made in sorting
proteins and nucleic
acids. A technique called
column chromatography
separates fragments of
nucleic acids or proteins
according to their size,
electrical charge, and
other important charac-
teristics. This process uses
a hollow column that is
filled with a material
through which the mole-
cules in a solution move
at different speeds. This
allows a researcher to

collect the molecules
separately as they pass
out of the column. If
necessary, additional
methods of purifying the
protein can then be used
and its biological activity
can be examined in detail.

Another technique,
called gel electrophore-
sis, uses electrical
currents to cause protein
or nucleic acid molecules
to travel through a semi-
solid gel according to
then- size and charge.

The separated molecules
can then be transferred
onto a sheet of special
paper, where various
methods can be used to
detect each molecule or
fragment. Electrophoresis
is especially useful for the
analysis and comparison of
samples containing many
different nucleic acid
fragments or proteins.

In addition to the above
techniques, cell biology
has been revolutionized
by recombinant DNA
technology. Often called
genetic engineering,
recombinant DNA tech-
nology enables scientists
to grow large quantities
of cells that have been
genetically altered to
make a particular pro-
tein (usually a protein
normally found in
another organism) and
then to harvest the pro-
tein from the cells.
Often, bacteria and
yeast cells are used to
produce these proteins.

Through the use of
recombinant DNA tech-
nology, scientists have
discovered many new
classes of genes and

proteins and are able to
compare the genetic
material of species as
different as humans and
bacteria. This helps
them determine the func-
tions of proteins and
regions within proteins
and to piece together
their roles in complex
systems. Recombinant
DNA technology has
been augmented by
another technique,
called PCR (polymerase
chain reaction), which
allows researchers to
make many copies of
DNA segments without
first having to grow these
segments in bacteria or
other organisms.

18

ASTONISHING UNIFORMITY OF LIFE

11 cells — whether
from a bacterium,
plant, mouse, or
human — are
made of the

same basic materials: nucleic
acids, proteins, carbohydrates,
water, fats, and salts. For this
reason, scientists seeking to
understand both normal and
disease processes in humans
can learn a great deal by
studying similar systems in
“model organisms” like
bacteria, slime molds, yeast,
and fruit flies.

physician and author Lewis
Thomas in The Lives of a Cell.
“It is from the progeny of this
parent cell that we take our
looks; we still share genes
around, and the resemblance
of the enzymes of grasses to
those of whales is a family
resemblance.”

“The uniformity of the earth’s
life, more astonishing than its
diversity, is accountable by
the high probability that we
derived, originally, from a

The genetic material in all liv-
ing cells is deoxyribonucleic
acid (DNA), a large molecule
that directs the making of
duplicate cells. DNA also
directs the building of proteins
according to a code. Even the
simplest living cells — the

mycoplasma — contain a rela-
tively large amount of DNA,
enough to code for perhaps
1,000 different proteins.
Every human cell has about 6
feet of very tightly wound
DNA strands contained
within its nucleus, and every
adult carries billions of miles
of ultrathin DNA strands in
his or her body.

!

Each cell is separated from
the rest of the world by a
membrane so thin that it

single cell,” noted the late

cannot be seen under a bght
microscope. Despite its thin-
ness, the surface membrane is
exceedingly sturdy, controlling
everything that goes into and
out of the cell and relaying
vital messages. Similar
membranes enclose or make
up a large number of the cell’s
organelles.

and cyanobacteria (blue-green
algae), do not have a mem-
brane around their nuclear
region. Eukaryotic cells, in
contrast, have two membranes
separating the nucleus from
the cytoplasm, as well as many
other internal membranes to
segregate their organelles.

The cells of all animals and
plants are eukaryotic.

higher eukaryotic organisms
are capable of differentiation
into many kinds of cells. This
gives eukaryotes certain
obvious advantages. However,
prokaryotes have advantages
of them own: simpler nutritional
requirements, resistance to
adverse conditions, and much
more rapid growth and division.

There is a fundamental
distinction between two of the
major categories of cells.
Prokaryotic cells, which
include bacteria, mycoplasma,

Only eukaryotic cells are able
to form large, multicellular
systems — an important step up
the evolutionary ladder. And
while, in general, prokaryotic
organisms produce only exact
duplicates of themselves,

The main job of most cells is
to manufacture proteins. In
eukaryotes, protein produc-
tion begins in the most
prominent organelle — the
nucleus.

19

u s

DIRECTOR OF PROTEIN SYNTHESIS

20

he nucleus is the
biggest, densest,
and most obvious
structure in the
eukaryotic cell —
the first to be recognized by
microscopists and the first to
be isolated in the biochemists’
centrifuge.

For many years, nobody
knew what the nucleus did. In
the 19th century, several
researchers noted that before
a cell divided, the nucleus
divided. But it was not until
the beginning of the 20th
century that scientists grasped
the connection between the
rodlike chromosomes (tightly
packed bundles of DNA and
proteins) that had been
observed in the nucleus and
the transmission of hereditary
traits. At that point, the
importance of the nucleus
became clear.

The nucleus is the cell’s
command center. The
chromosomes contain the
genes (made of DNA) that
give directions for every-
thing the cell is and will
he, and thus control the
cell’s reproduction and

heredity. DNA is a deceptively
simple molecule, consisting of
a sequence of subunits called
bases. The bases are linked
together to form a double
helix that can be visualized as
an immensely long,
corkscrew-shaped ladder.
Each rung in the ladder is
made up of two bases joined
together by chemical bonds,
and the ends of the rung are
attached to chains of chemically
bonded sugar and phosphate
molecules that are like the
upright rails of the ladder. A
unit of DNA containing one
sugar molecule, one phosphate
molecule, and one base is
called a nucleotide. There are
only four different bases:
adenine (A), thymine (T),
guanine (G), and cytosine (C).
They pair with each other

so that A is always joined to T
and G is always joined to C.
Thus, the sequence of bases
on one side of the ladder
(for example, AGCGT) is
complementary to, and deter-
mines, the sequence on the
other side (TCGCA). This is
the “genetic alphabet” — a
small set of “letters” with
which, as with the ABC’s, an
enormous number of messages
can be written.

As might be expected, the
nucleus is constantly active.
Before cell division, all of the
information contained within
the DNA must be duplicated
in a process called replication.
The speed with which replica-
tion occurs is astonishing. For
example, before a single
Escherichia coli (a common
intestinal bacterium, abbrevi-
ated E. coli ) splits in two,
which it does every 20 minutes,
the 360,000 turns of its DNA
helix must first be unwound.
Next, each of the 3.6 mil-
lion nucleotides on one
side of the DNA molecule
pulls away from its mate.
As the molecule unzips,
each half serves as a mold,
or template, for a new

Ribosome attaching to RNA

21

Lysosome

rete.

molecule. In a matter of min-
utes, a total of 7.2 million free
nucleotides are brought to
each template and attached A
to T and G to C. Finally, each
new double strand retwists
itself into a helix. (In
prokaryotes, such as E. coli ,
the DNA exists as a large,
single molecule rather than as
multiple chromosomes.)

All of this molecular maneuver-
ing must be performed both
rapidly and accurately. If
nucleotides are lost, rearranged,
or erroneously paired, the
garbled instructions that
result could lead to a non-
functioning protein when the
DNA’s code is translated.

/ 2 3 4

After replication in human
cells, the DNA condenses into
46 pairs of chromosomes. At
this point, the membrane sur-
rounding the nucleus breaks
down, the chromosome pairs
pull apart, and one member
of each pair moves to the
opposite pole of the cell. Then
the cell divides, forming two
identical daughter cells, each
with 46 chromosomes. The
production of sperm and egg
cells is a more complex process
in which a second division of
the nucleus occurs, resulting
in cells that have 23 chromo-
somes each, instead of 46.
When an egg is fertilized by a
sperm, the full complement of
46 chromosomes is restored.

Each of us begins as a single,
fertilized cell, a microscopic
package that contains within
its DNA the directions for
everything that we can
become. The single cell then
divides again and again. Each
new cell contains the same
kinds of molecules and even
the same amount of water as
the “parent” cell.

Some of our cells are very
short-lived and are repeatedly
replaced. Scavenger white
blood cells, for example, cir-
culate and consume invading
particles for only a few days
before they die. In contrast,
our brain cells never repro-
duce. Most live as long as we
do, but when one dies, it is
not replaced.

At any instant, only certain
genes in a cell are “on,” or
“expressed,” and giving
orders for the production of
specific proteins. Some of the
instructions that switch these
genes on or off are generated
as a result of interactions
between the surface membrane
and the environment. Thus,
the commands from the
nucleus are influenced by
what goes on outside the cell
as well as by the cell’s genetic
program .

An order to make a protein
begins when the appropriate
genes are transcribed from
the DNA into strands of
another kind of nucleic acid,
called messenger ribonucleic
acid (niRNA). Messenger
RNA is manufactured by
transcribing just one chain of

II <) 10 11

23

the DNA double hehx (one
side of the twisted ladder). A
strand of mRNA is comple-
mentary to the DNA from
which it is transcribed,
except that each adenine of
the DNA is paired with a
uracil (U), instead of with a
thymine. For example, the
stretch of DNA bases ATCG
is transcribed into the mRNA
sequence UAGC.

After additional processing,
the mRNA leaves the nucleus
through pores in the nuclear
membrane and carries its
message into the cytoplasm,
while the DNA remains safely
in the nucleus. Once in the
cytoplasm, the messenger
RNA moves to tiny organelles
called ribosomes, the factories
in which the next step of
protein manufacture, called
translation, takes place.

G

(( (I H H ii

18 19 20 21

To replicate before cell
division , the DNA double
helix separates and
unwinds and each strand
acts as a templa te for
the forma tion of a mirror
image according to the
rules of base pa iring: A
with T, and G with C.
This results in two
daughter DNA molecules
whose sequences are
identical to those of the
original DNA .

!

!r \i

22 X Y

13

14

15

16

17

24

Proteins, Workhorses Proteins are intensely

of the Cell studied by biomedical

researchers because
these molecules are
involved in nearly every
biological function.
Proteins include the
enzymes that allow the
chemical reactions
necessary to life to take
place efficiently. They
also include many of the
hormones that regulate
growth and development.
They are important
components of the cell’s
physical structure,
making up half of the
cell’s dry weight. They
help transmit messages
from nerve cells and
work in muscle cells to
convert chemical energy
into mechanical energy,
which permits movement.
Proteins in the cell
membrane control

molecules entering and
leaving the cell.
Hemoglobin proteins in
red blood cells transport
oxygen through the
bloodstream, and
antibody proteins fight
infection.

Proteins are made of
strings of amino acids
ordered according to
instructions contained in
the DNA. A protein’s
primary structure is this
linear chain of amino
acids; however, almost
immediately after it is
created the chain springs
into helices, sheets, or
other shapes that form
the protein’s secondary
structure. The shapes
then fold and coil fur-
ther into a complex,
three-dimensional
structure. This is the
active form of the protein
that can bind to, and
interact with, other
molecules.

The many proteins that
are enzymes act as
catalysts, speeding up
reactions without being
permanently altered
themselves. Without

enzymes, many

cellular processes would
proceed slowly or not at
all. According to chemist
Ronald Breslow of
Columbia University,
enzymes work so well
that a process that takes
5 seconds (such as read-
ing this sentence) with
enzymes would take
1,500 years without
them. Enzymes can do
their jobs — often, cutting
apart or splicing together
other molecules — over
and over. They also have
great specificity. Like a
lock, each enzyme will
accept only appropriately
shaped “keys” (called
substrates). Each cell
contains thousands of
kinds of enzymes.

Once a protein is purified,
the sequence in which
the amino acids occur on
the chain can be deter-
mined. Knowing the
amino acid sequence of a
protein is extremely
important for many
reasons. For example, it
may help scientists
synthesize large quantities
of the protein for
research or commercial
purposes. Direct sequenc-
ing of a protein, although
much quicker and more
accurate now due to the
development of automated
equipment, is an enor-
mously time-consuming
task. It is technically
easier to sequence the
DNA of the gene that
codes for the protein.

For this reason, in most
cases protein sequencing
has been replaced by
isolating, cloning, and
sequencing a gene by
recombinant DNA
techniques. The protein
sequence is then inferred
from the DNA sequence
that codes for it.

Even if the sequence of
amino acids in a protein
is known, scientists
cannot predict how the
protein will fold into its
final, active shape. Many
researchers are working
to solve this so-called
“folding problem.”

They feel that if they
can learn the rules by
which proteins fold, it
will open the way to
synthesizing engineered,
artificial proteins with
many therapeutic,
industrial, and manufac-
turing applications.

25

THE RIBOSOMES, PROTEIN FACTORIES

26

ibosomes, which
were discovered
in the mid-1950’s,
are extremely
tiny — less than
30 nanometers in diameter.
However, due to their crucial
role in protein manufacture,
ribosomes can also be
extremely numerous. In E.
coli , for example, ribosomes
account for one-fourth of the
cell’s mass. A ribosome is
made of two unequally sized
subunits, each of which is
composed of at least 40
different proteins and a form
of RNA called ribosomal RNA.

message of the mRNA not one
nucleotide at a time, hut
rather in groups of three.
These groups, called codons,
are like words. Each word
specifies one of the 20 different
amino acid subunits of a
protein or is a signal to start
or stop making a protein. For
example, the codon AGC in
mRNA is translated into the
amino acid serine, whereas
nucleotides in a different order,
say GCA, code for alanine.

The amino acids called for by
the mRNA are brought from
the cytoplasm to the ribosome

by a third kind of RNA,
transfer RNA (tRNA). This
small molecule is a connector:
One end carries three
nucleotides, known as the
anticodon, which will join to
a codon in the mRNA
according to the rules of base
pairing (A with U, and G with
C). The molecule’s other end
carries an amino acid. As the
mRNA passes through the
ribosome, tRNA brings the
correct amino acids in and
they are linked together by
chemical bonds to form a long
chain. When all the amino
acids for a protein are joined,
the chain is released.

During translation, a strand
of mRNA moves between the
two parts of a ribosome like a
piece of thread being pulled
through the eye of a needle.
The ribosome reads the

Each strand of mRNA can be
read many thousands of
times. Indeed, at any one
moment a strand of mRNA
containing the instructions
for a protein may be attached
to as many as 30 ribosomes.
Moreover, ribosomes work
very quickly to connect the

Complementary l)l\A strands

RNA strand

required amino acids into a
protein. Each ribosome in a
single E. coli , for example,
can link 15 amino acids in a
second. The speed and
efficiency of translation means
that each gene is capable of
directing the manufacture of
very large quantities of protein.
For instance, in each cell of a
sdkworm’s silk gland there is
a single gene that codes for
the protein fibroin, the chief
component of silk. Each time
it is activated, the gene can
make 10,000 copies of its
specific mRNA, and each
copy of mRNA can direct the
synthesis of 100,000 molecules
of fibroin. In 4 days, a silk
gland cell can manufacture a
billion molecules of fibroin!

This end
translated first

Ribosomes fall into two cate-
gories: those that are free in
the cytoplasm and those that
are bound to membranes. The
two kinds of ribosomes play
similar roles in the manufac-
ture of proteins. But while
the free ribosomes leave the
proteins equally free to float
in the cytoplasm, the bound
ribosomes transfer their
finished proteins into a large,
cobwebby organelle — the
endoplasmic reticulum.

Beginning of protein

Nearly completed protein

i RNA

In the nucleus, DNA’s
instructions are tran-
scribed (below left) into
a messenger molecule of
ribonucleic acid (RNA).
The code in a strand of
messenger RNA is
translated into a protein
(below right) in tiny
organelles, called
ribosomes, in the
cytoplasm.

27

Ribosome

EIN PROCESSOR

28

n 1945, as the electron
microscope was becom-
ing a useful research
tool, Albert Claude of
Belgium and Keith
Porter, who was then at The
Rockefeller Institute, used it
to discover a vast network of
channels bounded by mem-
branes in the cytoplasm of
chick embryo cells. At times,
this network looked like the
concentric circles of a slice of
onion. Porter called this net-
work the endoplasmic
reticulum (ER) because it was
more concentrated in the
inner (endoplasmic) region of
the cell than in the peripheral
(ectoplasmic) region. Similar
networks were later found in
all eukaryotic cells, except
mammalian red blood cells.

It was discovered that the
membranes of the endoplasmic
reticulum all interconnect,
forming a system of tubes and
flattened sacs. Some parts of
the endoplasmic reticulum
look smooth, while others
appear rough because they
are dotted with ribosomes
that form granules on their
outer surfaces.

The smooth endoplasmic
reticulum is involved in the
synthesis of fatty acids and
membrane components. This
ER also contains enzymes that
help detoxify and process
chemicals. It is especially
prevalent in liver cells.

Many of the proteins the
ribosomes of the rough endo-
plasmic reticulum synthesize
are intended to be exported
outside the cell. These proteins
carry specific amino acid
sequences, or “addresses,”
that allow them to enter the
inner space of the rough

endoplasmic reticulum, where
they undergo additional bio-
chemical modifications.

In the mid- 1950’s, George
Palade, then of The
Rockefeller Institute, con-
cluded that the amount of
rough endoplasmic reticulum
in a cell corresponds closely
to the quantity of protein the
cell exports. For example,
white blood cells that produce
infection-fighting immune
system proteins called anti-
bodies have highly developed
rough endoplasmic reticula.

Most of the proteins leaving
the endoplasmic reticulum are
still not mature; they must
undergo further processing in
another organelle, the Golgi
apparatus, before they are
ready to perform their
functions within or outside
the cell.

Electron micrograph
shows the folds of the
endoplasmic reticulum
thickly dotted with tiny
dark bodies, the
ribosomes.

29

Drawings show both the
ribosome-covered rough
endoplasmic reticulum
( top ) and the ribosome-
free smooth endoplasmic
reticulum (bottom).

THE GOLGI APPARATUS, FINAL PROTEIN SORTER

30

n 1898, the Italian sci-
entist Camillo Golgi,
who had been studying
stained owl and eat
nerve cells under his
light microscope, saw a cell
structure that did not look
like the nucleus. Although
some biologists at the time
thought the structure might
he an artificial one, perhaps
related to the stains that
Golgi had used, he believed
that the newly found
organelle played a role in
protein secretion.

In the 1960’s, Palade and his
colleagues confirmed Golgi’s
theory by using radioactive
labeling, staining, and elec-
tron microscopy to follow
proteins in pancreatic cells as
they moved from the rough
endoplasmic reticulum,
through the Golgi apparatus,
and into the secretory gran-
ules that carried them out of
the cell.

It is now known that each
Golgi apparatus consists of a
stack of flat, membranous
sacs that are piled one on top
of the other like dinner plates.
The stack is composed of

three distinct regions, and
each sac in the organelle con-
tains enzymes that modify
proteins as they pass through.
The sacs closest to the nucleus
receive vesicles (membrane-
hound sacs) filled with
protein molecules from the
endoplasmic reticulum. The
proteins must pass through
all the sacs in sequence to be
processed correctly.

The Golgi apparatus plays an
important role in transform-
ing many newly made
proteins into mature, func-
tional ones. Moreover, the
Golgi apparatus serves to
“package” certain proteins,
including enzymes and
hormones, into vesicles that
will later be secreted from the
cell. And finally, the Golgi
apparatus adds “addresses”
to proteins that are destined
to go to another organelle,
called the lysosome.

The elaborate organization of
the Golgi apparatus into sep-
arate compartments prevents
the release of thousands of
enzymes that, if mixed, would
result in uncontrolled bio-
chemical reactions inside
the cell.

31

Electron micrograph
opposite page ) and
Ira wing (below) show a
wries of cup-shaped
'(ICS making up a Golgi

LYSOSOMES AND PEROXISOMES, THE CELL'S "DIGESTIVE SYSTEM"

hen a white
blood cell
engulfs a
bacterium
and destroys
it, the white blood cell’s
lysosomes do most of the
work. They fuse with the
vesicle of engulfed material
and release digestive enzymes
to break up the material.
Similarly, when a cell takes in
large molecules of food,
enzymes in the lysosomes
break the food down into
smaller and simpler products
that the cell can use. These
products diffuse through the
lysosomes’ membranes
and go into the rest of
the cell, where they
serve as building
blocks for various
structures, until
nothing is left
inside the lysosomes
but indigestible
material, and the
lysosomes become
what are called
residual bodies. In
some cells, the residual

bodies then migrate to the
cell surface and eject the
undigested material into the
external environment.

Lysosomes were discovered
by a Belgian researcher,
Christian de Duve, in 1949,
when he homogenized some
animal cells and separated
them into various components
by using an ultracentrifuge.
After one of these components
had been left standing for a
few days, de Duve noticed

that the level of a certain
enzyme in it had risen
dramatically. Since this
enzyme had not attacked any
part of the cells before they
were ground up, he reasoned
that it must have been kept
segregated within the cell —
probably inside some kind of
organelle. He also knew that
he had used a relatively gentle
method of homogenization,
which could have allowed the
unknown organelle to remain
intact. Presumably, it
released its contents later.

De Duve’s biochemical
approach, for which he
shared the Nobel Prize
with Claude and
Palade in 1974,
was soon supple-
mented by electron
microscopy. But it
proved difficult to
identify the new
particles, since,
unlike other
organelles, lysosomes
vary in shape from
cell to cell. Finally, in

An electron micrograph
showing two small lyso-
somes and one large
lysosome. These
organelles contain
enzymes capable of
breaking (lawn various
substances.

1955, Alex Novikoff of the
Albert Einstein College of
Medicine clearly identified
some lysosomes in rat liver
cells, and it is now known
that lysosomes (whose name
refers to the fact that their
enzymes can lyse, or digest,
substances) exist in all
eukaryotic cells. In fact, lyso-
somes contain over 40
different enzymes that can
digest almost anything in the
cell, including proteins, RNA,
DNA, and carbohydrates.

At about the same time that
de Duve and his colleagues
were describing the bio-
chemistry of lysosomes, they
detected another enzyme-con-
taining organelle. In 1965, de
Duve proposed that the
organelle be called a peroxi-
some because it appeared to
both generate and break down

hydrogen peroxide, a corrosive
molecule composed of two
atoms each of hydrogen and
oxygen.

Today it is known that
peroxisomes exist in most
eukaryotic cells, and that
they are especially prominent
in mammalian liver cells. The
membrane that surrounds a
peroxisome is usually
permeable, permitting many
small molecules to enter easily.
Peroxisomal enzymes remove
hydrogen atoms from these
small molecules and join the
hydrogen to atoms of oxygen to
form hydrogen peroxide. One
of the peroxisomal enzymes,
catalase, then neutralizes the
hydrogen peroxide by cat-
alyzing its breakdown into

water and oxygen. This two-
step process is the method
that peroxisomes in the liver
use to break down molecules
of alcohol into substances that
can be eliminated from the
body. About one-quarter of the
alcohol that enters the liver is
processed in peroxisomes.

In his early descriptions of
peroxisomes, de Duve called
them “fossil organelles”
because of their primitive
nature and seemingly
expendable actions. (All of
the enzymes found in peroxi-
somes are also found

33

34

e cells in test
‘ enzyme and take

tide, but they are
n the Golgi (j). and

lerefoi

elsewhere in the cell.)
However, it is now known
that a rare, fatal genetic dis-
order called Zellweger’s
syndrome is the result of mal-
formed peroxisomes,
indicating that peroxisomes
do have a vital role in the
healthy cell.

The ability of peroxisomes
to use oxygen in chemical
reactions has led many
scientists to conjecture that
these organelles represent a
relic of an attempt by the

Golgi without enzyme

Lysosome

without

enzyme

6 6

Golgi apparatus Tag Enzyme

Lysosome

t Vesicles if

© ©

precursors of eukaryotic cells
to “cope” with oxygen as it
accumulated in the prehistoric
atmosphere. Peroxisomes
cannot, however, couple
oxygen use with energy pro-
duction. That ability is
restricted to mitochondria —
the “energy converters” of
eukaryotic cells.

Golgi with untagged enzyme

Empty

lysosome

o ©.

Vesicle

leaving

cell

1.

▲

No '***...

recapture

• • •

Untagged enzyme

I-cell disease

♦

%

f i ' \ "■

v&L

Tagged enzymes Lysosome with enzyme

added to cells in
test tubes

Hurler’s syndrome

r

Normal cell

Lvsosomes in Health
and Disease

If the cell does not pro-
duce a certain lysosomal
enzyme or if an enzyme
is not properly “addressed”
in the Golgi apparatus,
a lysosomal storage
disease can result. These
diseases are caused hy a
massive accumulation of
material that should
have heen digested in the
lysosome. Persons with
the lysosomal storage
disease known as
Hurler’s syndrome, for
example, cannot break
down large molecules of
sugar compounds called
glycosaminoglycans
because their lysosomes
do not contain the
enzyme iduronidase.
Glycosaminoglycans
accumulate in the lyso-
somes, swelling them so
much that the functioning
of the entire cell is
impaired.

A particularly severe
lysosomal disorder is
known as I-cell disease.
Children born with this
disease lack the entire
range of lysosomal
enzymes. The enzymes
are made, hut they are
dumped outside the cell
instead of being sent to
the lysosomes. Various
cellular nutrients thus
cannot be digested and
so pile up in dark lumps,
called inclusion bodies,
within the lysosomes.

The disease affects the
kidneys, heart, and
nervous system, and
children with it usually
die of heart failure or
pneumonia before reach-
ing puberty.

In the early 1970’s,
Elizabeth Neufeld, who
was then at the National
Institutes of Health,
showed that the lysoso-
mal enzymes of persons
with I-cell disease emerge
from the Golgi apparatus
without the chemical tag
they need to he directed
to the lysosomes. She also
showed that the defect
could be corrected in
test-tube cultures of cells

taken from people with
the disease. The corrective
factors she supplied were
the specific, properly
tagged enzymes that the
cells lacked.

Although enzyme
replacement therapy is
not being used to treat
people with lysosomal
storage diseases like
Hurler’s syndrome, it is
being used to treat a
different group of disor-
ders called lipid storage
diseases. Enzyme
replacement therapy for
many disorders presents
challenges to researchers,
however, because purified
enzymes injected directly
into the body tend to he
quickly destroyed or
inactivated. It is particu-
larly difficult to get
enzymes into brain
cells — an important
problem now under
investigation, since
several lysosomal storage
diseases produce severe
mental retardation.

I T

OCHONDRIA, ENERGY CONVERTERS IN THE CELL

M

III

36

ne and a half
billion years
ago, scientists
believe, eukaryotic
cells derived the
energy they needed through a
variety of relatively inefficient
processes, none of which
required oxygen. Oxygen, a
waste product of some of these
processes, gradually began to
accumulate in the atmosphere.
It was at this time, scientists
hypothesize, that a primitive
eukaryotic cell engulfed a
primitive bacterium that had
acquired the abdity to use
oxygen to produce large
quantities of energy. Over the
eons, a symbiotic relationship
evolved between the cells, and
today almost all plant and
animal cells have organelles
that are the descendants of the
primordial energy producers.
In animal cells, these

organelles are called mito-
chondria. Plant cells have
both mitochondria and a sec-
ond kind of energy-producing
organelle, the chloroplast.

Chloroplasts use the energy in
sunlight to convert molecules
of carbon dioxide and water
into molecules of sugar, a form
of energy that can be stored in
the plant cell. (Oxygen is
given off as a byproduct of
this process, which is called
photosynthesis.) When an
animal eats a plant (or
another animal that has itself
eaten plants), the plant’s
sugars are broken back down
into carbon dioxide and
water, with the help of oxygen
and an arsenal of enzymes,
releasing large amounts of
stored energy. This energy is
immediately converted to yet
another form — molecules of
adenosine triphosphate (ATP).

ATP is often called the
universal currency of cellular
energy. It is a convenient way
for cells to store the energy
they need for such processes
as protein manufacture, DNA
replication, and the construc-
tion of new organelles. ATP is
also required for such
mechanical work as muscle
contraction, pumping water
through membranes, and cell

movement. Following the first
stages of sugar breakdown,
the complicated process of
energy transfer from sugar to
ATP takes place within the
animal cell’s mitochondria.

Besides supplying energy,
mitochondria help to control
the concentration of calcium
and other electrically charged
particles in the cytoplasm.
They also break down and
recycle the energy contained
in fatty acids and amino acids.

Mitochondria are the largest
organelles in an animal cell,
after the nucleus, yet some
cells have more than a
thousand of them. They vary
in diameter from 0.5 to 1
micrometer and in length up
to 7 micrometers, and can
be seen with a good light
microscope. Mitochondria are
usually represented as
oval-shaped, but in life they
can change shape quite readily.
They swell or contract in
response to various hormones
and drugs and during ATP

manufacture. This swelling
and contracting appears
related to the movement of
water through cells, and is
particularly evident in the
kidneys, through which 180
liters of blood are filtered
daily.

Although mitochondria were
first observed in the 1880’s, it
took many years for scientists
to understand the organelles’
function. The process by
which mitochondria use oxygen
to release the chemical energy
stored in food is called cellular
respiration. In the early
1900’s, it was discovered that
the biochemical reactions of
this type of respiration fall
into two main groups: the
carbon pathway, in which
sugar is broken down into
carbon dioxide and hydrogen;
and the hydrogen pathway,
which transfers hydrogen to
oxygen in stages, forming
water and releasing energy.

In the
hydrogen
pathway,
the hydrogen’s
electrons pass through
an “electron transport chain”
made up of enzymes. As they
move from enzyme to enzyme,
the electrons give up part of
their energy. This energy is
then stored in molecules of
ATP. In the end, 38 molecules
of ATP are formed for every
molecule of sugar that is used
up in respiration.

Electron micrograph
showing one of the cells
many mitochondria , the
organelles that convert
energy from food into a
form that can be stored.

Mitochondria are marvelously
efficient at converting the
chemical energy of sugar into
ATP. Whereas an engine
would be considered very
efficient if it converted 25
percent of the energy available
in gasoline into mechanical
work, mitochondria routinely
turn 54 percent of the available
energy in sugar into ATP.

This efficiency is achieved, in
large part, because of the
mitochondria’s internal
structure. In the early 1950’s,
Palade and a Swedish scientist,
Fritiof Sjostrand, reported
that mitochondria are
surrounded by a membrane
and that they have a system
of parallel, regularly spaced
inner ridges that the scientists
named “cristae.” It is now
known that there are two
membranes around a
mitochondrion: an outer
membrane, separated from
the rest of the organelle by a

fluid-filled gap; and an inner
membrane that is folded
inward in many places to
increase its surface area, form-
ing the cristae. This ridged
surface allows the enzymes of
the electron transport chain,
which are attached to the
cristae, to be packed more
densely within each mitochon-
drion, thus increasing the
organelle’s efficiency. This
general design seems to have
existed unchanged from the
time that mitochondria-like
cells were free-living organisms.

Mitochondria have also kept
other vestiges of their existence
as independent organisms.

For example, mitochondria
“reproduce” by splitting in
half, as many modern bacteria

Inner membrane

do; they are not formed by
budding from existing cellular
structures or built up from
simple cellular constituents,
as is the case for ribosomes.

More significantly, after a
billion or so years of residence
within “host” cells, mitochon-
dria (and chloroplasts) still
retain some of their own
DNA. The amount of this
non-nuclear DNA varies
significantly from organism to
organism. The chloroplasts of
plants, for example, have five
times more DNA than do the
mitochondria of mammalian
cells. Human mitochondrial
DNA is a circular molecule

Outer membrane

16,569 nucleotide pairs long.
Although this is less than 1
percent of the total DNA in a
human cell, each mitochon-
drion has enough DNA to
code for several of its key
inner membrane proteins and
its own rihosomal proteins.
(All of the other proteins in a
mitochondrion are coded for
in the nucleus, made on free
ribosomes in the cytoplasm,
and imported into the
organelle.)

Another curious characteris-
tic of human mitochondria is
the fact that all of a person's
mitochondria are descendants
of those of his or her mother;
no paternal mitochondria are
present. This fact has proved
useful to evolutionary
biologists, who can study the

passage of mitochondrial
DNA from generation to
generation while ignoring the
“interfering” information
contained in the nuclear
DNA, which records the
genetic contributions of both
parents.

Scientists have long suspected
that defects in mitochondrial
genes could lead to inherited
disease in the same way that
mistakes in nuclear DNA do.
This hunch was not proven
until 1988, when Douglas
Wallace of Emory University
showed that a rare eye disease
called Leber’s hereditary
optic neuropathy is caused by
a mutation in mitochondrial
DNA. The defective mito-
chondrial gene prevents the
optic nerves from producing
enough ATP and the nerves,
which need huge amounts of
ATP and are thus particularly

sensitive to any deprivation,
die. When he announced
these findings, Wallace said,
“We feel that these alterations
[in mitochondrial DNA] may
be responsible for a wide
spectrum of diseases in the
brain, the central nervous
system, and the musculoskele-
tal system.”

Mitochondria, chloroplasts,
and the other organelles
described thus far are
surrounded by membranes.
But cells can also contain
threadlike organelles that
lack membranes. These
extremely fine structures
serve as buttresses, highways,
and movement mechanisms
for the cell.

39

A mitochondrion is
shown us if it hud been
sliced longitudinally.
The inward folds of the

THE CYTOSKELETON, THE CELL'S PHYSICAL PROPS

40

Iany cells in a
multicellular
organism
must combine
the seemingly
contradictory traits of stabil-
ity and mobility. With few
exceptions, multicellular
organisms begin to develop
when a motile sperm meets an
egg. Many cell divisions
occur, and then cells migrate
to their final positions.

During life, individual cells
divide frequently, and certain
specialized cells move through
the body to accomplish vari-
ous tasks. In addition, every
cell must have a mechanism
for moving materials within
itself. Balancing the need for
movement is the cell’s need to
maintain its shape against
the pressure of sur-
rounding cells.

Keeping a cell
firm while

enabling it to move are the
twin roles played by the
cytoskeleton.

For a long time, microscopists
believed that the cytoplasm
surrounding the cell’s
organelles was completely
unstructured. But as scientists
began to use newer and
gentler fixatives to prepare
cells for electron microscopy,
a lacy network of fibers was
revealed. These structures
crisscross the cell like girders
and it was hypothesized (and
later shown experimentally)
that, like an animal’s bony
skeleton, these structures
play a role in giving the cell its

shape and support. For this
reason, they are known col-
lectively as the cytoskeleton.

There are three main kinds of
cytoskeletal fibers- — microfila-
ments, microtubules, and
intermediate filaments —
which are distinguishable
both by their structure and
by their protein composition.
All three support and stiffen
the cell. In addition to their
structural roles, microtubules
and microfilaments are
essential for a variety of
dynamic, whole-cell activities,
including division, contraction,
and crawling, as well as for
the movement of vesicles and
chromosomes within the cell.

Microfilaments are more
commonly called actin fila-
ments because they are
composed of “beads”
of the protein actin

|T stained with modified anti-
bodies that attack to the ceils
■scaffolding, ' called the cytoskeleton,
and that alow in response to a specific wave-

length of light.

arranged into long, slender
chains. Each filament is only
6 nanometers in diameter;
they are the thinnest of the
cytoskeletal components. The
role that actin filaments play
in muscle contraction has
been thoroughly studied over
the past 40 years. In the
1950’s, a British scientist, Hugh
Huxley, proposed a model for
muscle contraction that has
since been shown to be cor-
rect. According to the model,
each muscle cell comprises
parallel rows of actin filaments
that alternate with rows of
another protein, myosin.
When stimulated by an influx
of calcium, projecting “arms”
of myosin “grab” the adjacent
actin filaments and pull,
causing the muscle cell to
shorten. Contraction is an
ATP-reqniring process; each
“grab” and release by a
myosin molecule uses up one
molecule of ATP. In recent
years, researchers have found
evidence of similar actin-
myosin interactions in many
other kinds of cells, including
cells that secrete hormones
and white blood cells that
move through the body to
fight invading organisms.

Microtubules, at 22 nanome-
ters in diameter, are the
thickest of the cytoskeletal
components. They were
noticed in the mid-1950 s, but
were seen only rarely until
1963, when the gentle fixative
glutaraldehyde was developed.
Each hollow tubule is composed
chiefly of small, spherical
subunits of proteins called
tubulins. Microtubules
assemble spontaneously from
“pools” of tubulin when
needed and, under appropriate
conditions, dissolve back into
their tubulin subunits.
(Microfilaments also form and
break down spontaneously.)

The microfilament
bundles in this skin cell
have been stained with
modified antibodies that
glow in response to a
specific wavelength of
light.

41

Under the microscope, micro-
tubules can be observed
growing and shrinking rapidly.

One of the most vital functions
of microtubules is to aid in
cell division. Just before a
cell divides, small bodies
called centrosomes (which are
themselves composed of
microtub ule-like fragments)
migrate to the cell’s poles. An
oval-shaped bundle made of
microtubules forms between
the centrosomes. Chromosomes
attach to the bundle, which
then helps to guide them to
the daughter cells. In 1988,

Kinesin

Marc Kirschner, who was
then at the University of
California, San Francisco,
and his colleagues found strong
evidence that chromosomes
move toward the poles as the
microtubules slowly dissolve.

Between cell divisions,
microtubules act as miniature
highways along which vesicles
carrying such materials as
hormones, neurotransmitters,
and nutrients move. Using
new techniques, such as
video-enhanced light
microscopy, scientists in
several laboratories have
observed microtubules inter-
acting with a protein called
kinesin that functions as a

vesicles and organelles along
microtubule “tracks” toward
the cell surface. Kinesin also
moves vesicles filled with
neurotransmitters along the
microtubules within nerve cell
axons. A second, more
recently discovered motor
protein, called dynein, moves
vesicles in the opposite direc-
tion, toward the cell’s interior.

Microtubules are also involved
in the movement of cilia and
flagella. These whiplike
filaments project from certain
cells and perform a variety of
tasks. Large numbers of cilia
are found on cells that line
the respiratory tract, for
instance, where they help to

reproduction. The coordinated
beating of cilia in the oviduct
produces a sort of current
that draws the egg into the
uterus, while the rapidly
thrashing flagella of sperm
help them to “swim'” toward
the egg.

The inherent ability of micro-
tubules and microfilaments to
assemble and disassemble
rapidly allows for the construc-
tion and destruction of these
cytoskeletal components to
suit the needs of a moving
cell. In contrast, intermediate
filaments are the most stable
of the cytoskeletal fibers. At 8
to 10 nanometers in diameter,
they are intermediate in size
between microfilaments

and microtub ides. Intermediate
fdaments are strong and are
found in cells that require or
provide mechanical strength,
such as those of the skin and
intestines. It is believed that
these filaments also have
other important functions in
cell physiology, and researchers
are studying the cause and
effect of their alteration
during disease.

Current investigations of the
cell’s organelles — the nucleus,
ribosomes, endoplasmic
reticulum, Golgi apparatus,
lysosomes, peroxisomes,
mitochondria, and cytoskele-
ton — hold great promise for
the solution of problems in
basic biology and clinical
medicine. However, the key
that may unlock the greatest
number of health benefits
may well be found in the
cell’s filmy membranes,
particularly the surface mem-
brane, which plays a pivotal
role in maintaining the
integrity of the cell and, in a
larger way, in protecting the
health of the organism.

Some microorganisms
are equipped with a
flagellum ( composed of
microtubules), which
thrashes to propel the
animal.

THE SURFACE MEMBRANE, VERSATI

44

Tn the beginning,'’’

wrote biologist Gerald
Weissmann, “there
must have been a
membrane! Whatever
flash of lightning there was
that organized purines,
pyrimidines, and amino acids
into macromolecules capable
of reproducing themselves, it
would not have yielded cells
but for the organizational
trick afforded by the design
of a membrane wrapping.”
Weissmann imagines these
primitive membranes forming
bubbles in which the first
macromolecules were enclosed
and protected from dissipation
in the salty primordial seas.

A cell’s outer membrane is
often thought of as a bound-
ary that distinguishes the
living cell from its surround-
ings. And, indeed, surface
membranes are crucial in

keeping cells intact. Moreover,
the internal membranes that
wrap around many organelles
in eukaryotic cells separate
the cytoplasm into discrete
regions, somewhat like the
walls that form rooms in a
house. These inner membranes
enable the cell to perform
many otherwise incompatible
biochemical activities simulta-
neously, thereby greatly
increasing the cell’s efficiency.

Yet despite its barrier func-
tions, the cell membrane —
which is often less than 0.01
micrometer thick — is not
impassive. Rather, it is
exquisitely sensitive to its
surroundings and selectively
allows certain substances to
enter and leave the cell while
barring others. It takes in
nutrients and excretes wastes.
It sends and receives chemical
and electrical messages,
including signals for the cell
to manufacture proteins or to
divide. In multicellular
organisms, it joins with other
cells to form tissues.

LE GATEKEEPER

These myriad abilities are
due to the membrane’s com-
position. Although surface
membranes differ in their
precise composition depend-
ing on the cell’s type, and
although a membrane’s con-
figuration changes from
moment to moment, all mem-
branes are composed of two
basic kinds of molecules —
proteins and lipids (fats).

In 1972, S. Jonathan Singer
and Garth Nicolson of the
University of California, San
Diego proposed a model to
describe the relationship of
proteins and lipids in an ide-
alized membrane. They
compared the proteins to
“icebergs floating in a sea of
lipids,” and suggested that
some of the proteins are
folded so that the “tips” poke
above and below the plane of
the membrane, while the mid-
dle of the protein is
embedded in the membrane
itself.

Although such tripartite pro-
teins were unknown at the
time Singer and Nicolson
proposed their model, they
have since been shown to play
important roles in a number
of biological processes,
including those that involve
the transport of molecules
into the cell. Many other
membrane proteins that are
attached either to the inner
or outer face of the surface
membrane have also been
studied in detail in the years
since Singer and Nicolson
proposed their so-called
fluid-mosaic model.

The lipids that make up the
bulk of a cell’s surface mem-
brane fall into three classes:
phospholipids, steroids
(primarily cholesterol), and
glycolipids. About half of the
molecules in an average
membrane are phospholipids.
Each phospholipid molecule
has a water-seeking phosphate

Lipid “ tail ”

“head” and two flexible,
water-avoiding lipid “tails.”

In a surface membrane,
phospholipids spontaneously
arrange themselves into a
double layer with the phosphate
heads touching the watery
interior and exterior of the
cell, and the lipid tails buried
in the middle of the layer.

Cholesterol is a rigid molecule
that helps stabilize the mem-
branes of animal cells. It is
manufactured within the cell
(in the endoplasmic reticulum)
and is also brought into the cell
from the blood. Cholesterol is
present only in animal cells;
plant cells are stiffened by a
very rigid cell wall composed
mainly of cellulose.

Proteins

is. Surface

Glycolipids are composed of a
sugar (“glyco” is derived
from the Greek word for
sweet) and a lipid portion,
and make up about 5 percent
of the lipid population. A
person’s blood group (0, A,
B, or AB) is determined by
the particular kind of
glycolipids present on the
surface of his or her red
blood cells.

45

ig keeping the

suostances to

enter and leave the cell.

DIRECTING TRAFFIC ACROSS THE SURFACE MEMBRANE

46

he oily lipids of a
cell’s surface
membrane serve
admirably to
prevent the cell’s
water-soluble contents from
leaking out. However, in pre-
venting such leaks, the cell is
confronted with another
problem — how to transport
wastes and cell products out
of the cell and allow nutrients
and other substances in,
without either shrinking or
swelling too much.

Over eons, cells have evolved
a wide variety of transport
mechanisms to ferry sub-
stances across the membrane.

Transport may be either “pas-
sive,” which requires no
energy, or “active,” which
uses ATP. Also, a molecule
may either pass directly
through the membrane (usually
through a pore created by a
specific transmembrane pro-
tein) or it may be carried in
when a bit of the surface
membrane folds inward
around the entering particle,
then pinches off and carries
the particle into the cell. The
method used to import a sub-
stance depends on a
combination of its size, chem-
ical composition, electrical
charge, abundance, and abil-
ity to dissolve in lipids.

Oxygen, nitrogen, and other
small molecules that can dis-
solve easily in lipids move
readily back and forth across
the membrane. Importantly,

because of its small size and
the distribution of its electri-
cal charge, a water molecule
can also pass relatively easily
through the membrane even
though water is quite insolu-
ble in od.

In contrast, large molecules,
such as proteins and sugars,
cannot pass through the
membrane unassisted. A vari-
ety of transport systems,
many of which involve sur-
face proteins, are used to
ferry these substances into
and out of the cell. Surface

membrane lipids are also
highly impermeable to all
electrically charged molecules,
no matter how small they are.
ATP-requiring protein “pumps”
are employed to transport
these particles, which are
called ions.

One well-studied pump sys-
tem is the sodium-potassium
pump. This membrane
protein consumes more than
a third of the cell s total ATP

production in an endless
cycle of pumping sodium ions
out of the cell while drawing
potassium ions in. The differ-
ence in ion concentration
inside and outside the cell
creates a source of potential
energy that can be used for a
variety of tasks, including the
propagation of electrical
signals in nerve cells.

47

Sodium ion outside cell

Direction of
potassium
movement

i Cell surface membrane

J

Direction of
sodium movement

Potassium ion inside cell

GNAL TRANSDUCTION, THE JOB OF R

48

lie unique char-
acteristics of a
cell depend, in
large measure, on
what kinds of

receptor proteins it has. Like
a lock that accepts only an
appropriately shaped key, each
different receptor will function
only when the correctly
shaped blood-borne molecule
(called a ligand) attaches to it.

Many hormones exert their
effects through receptor proteins
that transfer the signal and
generate “second messengers”
within the cell. One of the best
understood of these second
messenger systems employs
proteins called G proteins.

In the G protein system, when
a “first messenger” (such as a
hormone) reaches the cell surface,
it hinds to a receptor that then
sends a signal to a G protein

located on the interior side of
the cell membrane. Depending
on its type, the activated G
protein then either stimulates
or inhibits the activity of any of
a number of enzymes, including
one called adenylate cyclase.
Stimulating this enzyme causes
cyclic AMP, a common second
messenger, to be produced.
Cyclic AMP then sets off a
chain reaction that eventually
results in changes in the shapes
of certain proteins in the cell,
which, in turn, lead to still
other cellular responses. When
levels of the first messenger
drop, the G protein “switches
off’ and the response terminates.

The cell appears to employ
this complex signaling system
because it increases both the
efficiency and speed of message
transmission. A single incoming
messenger molecule triggers a
cascade of reactions that even-
tually results in a large
amplification of the original
message. Furthermore, the time
elapsed between the arrival of
a signal at a G protein and a
cellular response is often only
a few fractions of a second. For

CEPTOR PROTEINS

example, light-sensitive eye cells
respond to as little as one
photon of light in just a few
milliseconds through a G
protein-mediated system. In
contrast, other cells take as
long as 30 seconds to respond
to signals from the environment.

Certain diseases impair the
functioning of the second mes-
senger system and cause
profound cellular malfunction.
A toxin produced by the
organism that causes cholera,
for example, “locks” the G
proteins of intestinal cells into
the “on” position so that they
are constantly stimulating the
production of cyclic AMP.

This causes vast amounts of
fluid to cross the fining of the
gut, causing the often-fatal
diarrhea associated with
cholera.

I low a signal brought to
the cell by a single message
molecule is amplified
through the second

messenger sys tern

Step

Action

Product

49

Message

A message molecule binds to
a receptor and activates it.

Each activated receptor
activates many G proteins
(two shown), which each
activate one molecule of the
enzyme adenylate cyclase.

Using ATP. each molecule
of adenylate cyclase make :
many molecules of cyclic

AMP.

Receptor

Cell membrane

Activated

adenylate

cyclase

G protein

Cyclic AMP

kinase.

Each protein kinase
molecule activates many

cule

of

1

A

A

*

A

A

V

V

?in

in

m

i ii

in

m

/II

m

/ii

/h

in

/i\

III

M l

1 1 1

n i

/ 1 1

/ 1 \

/ 1 1

I l V
I l \

/ I I
/ I i
I l l
/ I i
/ l 1

I It
l l l
I l I
/ I l
/ I I
/ l l
/ I \

/ I l
/ I I
/ I l
l I I
/ I l
' I i

i H!

1 1 i
1 1 \

;l I l
I I l
I I t
/ I 1
I I '

/ I \

I I \

I I t
I I V
I I 1
I I 'V:

I I '

I I 1
I I 1.

/ I \

I I 1
/ I 1
/ I '

/ I l

molecules of an enzyme

Each copy oj the activated
enzyme carries out its
function.

Activated
protein kinase

Activated enzyme

Products of
enzyme

50

A Breakdown in the
LDL System Can Mow
Be Treated

The low-density lipopro-
tein (LDL) system works
like a thermostat to
ensure that the cell
always has enough cho-
lesterol for life and
growth, without accumu-
lating too much of it.
Because of a defective
gene, however, the cells
of people with familial
hypercholesterolemia
(FH) are severely deficient
in LDL receptors. Their
livers manufacture
cholesterol and release it
into the blood, but since
their cells do not have
enough LDL receptors,
not enough cholesterol is
taken up. Instead, it begins
to clog their arteries.

People who have two
genes for FH suffer from
heart disease from a very
early age, sometimes as
early as age 1. Persons
with only one defective
gene do make some LDL
receptors, but still have a
high risk of heart attacks,
and often have an attack
before age 30. FH is a
relatively common
genetic disorder; as many
as 1 person in 500 carries
one copy of the defective
gene.

Michael Brown anti
Joseph Goldstein of the
University of Texas
Health Science Center at
Dallas determined both
the precise genetic
defects and the role of
the LDL receptor in FH.
In 1985, both men were
awarded Nobel Prizes
for this work. Their
studies also led to the
development of lovastatin,
a drug to treat FH.
Lovastatin has a dual
action: It reduces the
liver’s ability to manu-
facture cholesterol so
that fewer LDL’s enter
the bloodstream, and it
causes the LDL receptors
that the person has to
take up cholesterol more
efficiently.

The mechanism Brown
and Goldstein outlined for
LDL receptors is but one
example of the process of
receptor-mediated mem-
brane transport. The
cell also uses protein
receptors to bind or take
in such substances as
insulin, transferrin (an
iron-bearing compound),
and cell complexes that
are produced when the
immune system is
activated.

A LOOK TOWARD THE FUTURE

7e are deeply
indebted to the
scientists of the
past who first
mm revealed the mar-
vels of the cell. As productive
as the past has been, however,
the future promises to be still
more exciting as researchers
gain an even greater under-
standing of cell activities and
apply that understanding to
questions of health and disease.

In the three centuries since
Robert Hooke turned his micro-
scope on hits of dried cork,
much has been learned about
the world inside the cell.
Directed by the genes and influ-
enced by the environment, cells
perform an astonishing array of
tasks and take on a variety of
forms suited to their work. Cell
biologists now know a great deal
about how the cell’s living
machinery works to make
proteins. In addition, they are
learning the molecular details of
many of the biochemical processes
critical to the life of the cell.

Scientists are also making
progress in understanding how
molecules outside the cell influ-
ence what goes on inside and
how cells within an organism
communicate with each other.
One clinical application of this
work will probably be better
ways to treat chronic wounds
and burn injuries.

We now have a much more
complete understanding of the
molecular signals that cause cells
in an embryo to differentiate into

muscle, blood, nerve, and other
specialized cells. Additional
knowledge about cell differentia-
tion will provide greater
understanding of normal and
defective development in humans.

In recent years, many genes
involved in hereditary diseases
have been identified. The ability
to isolate and copy these genes
allows biologists to study what
goes wrong in cells to cause the
diseases. In addition, researchers
are working to determine the
sequence of all of the DNA —
the genomes — of entire organ-
isms, including humans. This
will permit many new studies
and should lead to important
information on cellular processes
and how they are coordinated.

Scientists are working on many
techniques to correct faulty
genes, including ways to sneak
new nucleotide sequences past
the body’s defense mechanisms.
The goal, once the sequences
are taken up by the cell, is to
get them integrated in such a
way that the desired substances
are properly made. Gene
therapy is also beginning to be
employed in new and creative
experiments that may someday
lead to new ways of treating
many different disorders. In
the future, it may be possible
to use it to genetically engineer
living cells to make their own
“medicines” in response to
carefully controlled chemical
signals from outside the cell.

New techniques to rapidly
screen chemical compounds are

now greatly expanding the pool
from which possible therapeutic
substances can be drawn. The
study of molecular structures
by x-ray crystallography has
yielded detailed understanding
of many molecules critical to
health, and may eventually yield
therapeutic molecules specifi-
cally tailored to “fit” the
structures and thus alter their
chemical activity. In addition,
the science of synthetic chem-
istry has yielded many improved
ways to design new therapeutic
substances. The success that all
these promising achievements
will have in the fight against
disease depends on continued
progress in understanding
cellular biology.

These advances are only a
beginning, because the cell still
holds many mysteries. It some-
times takes years after a new
discovery is made for the
potential applications to
become clear. Thus, just as no
one can predict what basic
researchers will discover in the
future, neither can the even-
tual clinical applications of
today’s results be known.

Scientists now have an unprece-
dented array of tools and body
of knowledge with which to work.
A wealth of exciting avenues
for scientific exploration are
opening. If the momentum can
be sustained, the next 50 years
may well see victories over
many human diseases.

51

GLOSSARY

Amino Acid A building block of proteins. There
are 20 different kinds of amino acids; a protein
consists of a specific secpience of amino acids.

Angstrom A unit of length, one hundred-millionth
of a centimeter (approximately 0.000000004
inch); used for describing atomic dimensions.

ATP (adenosine triphosphate) The compound that
serves as a source of energy for the physiological
reactions in cells.

Bacterium A one-celled microorganism that
contains no nucleus.

Base The basic subunit of DNA or RNA. Paired
bases— adenine with thymine and guanine with
cytosine (uracil replaces thymine in RNA)— make
up each “rung” of the “ladder” of the DNA
molecule. See nucleotide.

Basic Research Scientific research that seeks to
discover how systems work and develop a base
of knowledge that other scientists can use in
order to achieve practical goals, such as
treatments or cures for diseases.

Biochemistry The study of the chemical reactions
that occur in living organisms.

Cell The basic subunit of any living organism; the
simplest unit that can exist as an independent
living system.

Cell Cycle The sequence of events by which the cell
duplicates its contents and divides into two.

Cell Surface Membrane A complex film of lipids
interspersed with proteins. It covers the cell,
maintains its integrity, and controls what goes in
and what comes out.

Centrifuge A machine that separates particles

according to their si/a* and density by spinning
them at varying speeds.

Chloroplast The chlorophyll-containing organelle
in green plants in which light energy is converted
into sugars.

Cholesterol A waxy lipid produced by animal cells
that is a prominent component of cell membranes.

Chromosome A rod-shaped structure containing
genes that is found in the cell nucleus. It is
composed of DNA and proteins, and can be seen
in a light microscope during some stages of cell
division.

Codon A sequence of three consecutive nucleotides
in a DNA or RNA molecule that codes for 1 of
the 20 amino acids in proteins or for a signal to
start or stop protein production.

Column Chromatography A technique used to
separate the components of biologically active
molecules, which move at different speeds
through a hollow column that is filled with a
chemically reactive material.

Cristae The inward folds of a mitochondrion’s
inner membrane.

Cyanobacteria (formerly called blue-green algae)
Single-celled organisms that perform a type of
photosynthesis.

Cytoplasm All the substance inside a cell, excluding
the nucleus but including the other organelles.

Cytoskeleton A group of non-membrane-bound
organelles that supports the cell. Some serve
as conduits for the transport of various cell
components.

Differentiation The series of biochemical and

structural changes that groups of cells undergo
in order to form specialized cells and tissues.

DNA (deoxyribonucleic acid) The substance of
heredity; a large molecule that carries the
genetic information necessary for all cellular
functions, including the building of proteins.
DNA is composed of the sugar deoxyribose,
phosphate, and the bases adenine, thymine,
guanine, and cytosine.

Electron Microscope A powerful microscope that
uses beams of fast-moving electrons instead of
light waves to enable objects to be observed.

Endoplasmic Reticulum An organelle made up of
membranes that form a system of tubes and
flattened sacs. Some of the membranes are
smooth (the smooth endoplasmic reticulum);
others are rough (the rough endoplasmic
reticulum) because they are dotted with ribosomes.

Enzyme A substance (usually a protein) that speeds
up, or catalyzes, a chemical reaction without
being permanently altered or consumed.

Eukaryotic Cell A cell that has a true nucleus sur-
rounded by a membrane. This group includes all
animal and plant cells, except cyanobacteria.

Fluid-Mosaic Model A model of the cell surface
membrane in which proteins move about within
a bed of semi-fluid lipids.

G Protein One of a group of proteins involved in
signal transduction within the cell.

Gel Electrophoresis A technique used to separate
molecules according to their sizes and charges.

Gene A unit of heredity; a segment of the DNA
molecule containing the code for a specific
protein product or function.

Genetic Engineering See recombinant DNA
technology.

Glycolipid A molecule composed of sugar and
fat that forms an important component of cell
membranes.

Golgi Apparatus An organelle composed of

membranous sacs that packages proteins into
vesicles and sends them to the cell’s surface or
to lysosomes.

Intermediate Filament A component of the
cytoskeleton that acts to strengthen the cell.

Ion Any atom or molecule that contains an unequal
number of electrons and protons and, therefore,
carries a net positive or negative electrical charge.

Ligand Any molecule that hinds to a specific site
on a protein or other molecule.

Light Microscope An instrument that magnifies
objects using curved lenses and white light as a
source of illumination.

Lipid A fat or fat-like compound.

Lysosoine A small organelle containing powerful
enzymes that can digest a variety of materials.

Microfilament A threadlike organelle involved in
cell motion, particularly muscle contraction.

Micrometer (or micron) One one-thousandth of a
millimeter; 10,000 angstroms; convenient for
describing the dimensions of cells and organelles.

Microtubule A thin, tubular organelle that acts as
a structural support for the cell. During cell
division, microtubules form the spindle that
directs chromosomes to the daughter cells.

Mitochondrion The cell organelle that converts the
energy in sugars into ATP, thereby fueling the cell.

Molecule The smallest physical unit of an element
or compound. A molecule of an element consists
of one or more identical atoms. A molecule of a
compound consists of two or more different atoms.

Multicellular Made up of many cells.

Nanometer One one-thousandth of a micrometer.

54

Nucleic Acid Either of two kinds of molecules
(DNA and RNA), formed by chains of
nucleotides, that carry genetic information.

Nucleotide A subunit of DNA or RNA that includes
one base, one phosphate molecule, and one
sugar molecule (deoxyribose in DNA, ribose in
RNA). See base.

Nucleus In eukaryotic cells, the membrane-bound
organelle that contains the genetic material.

Organelle A specialized structure having a definite
function in a cell; for example, the nucleus, a
mitochondrion, a ribosome.

Peroxisome A membrane-bound organelle that both
generates and breaks down hydrogen peroxide.

Phospholipid A fatty compound that contains

phosphate. Phospholipids make up much of the
outer membranes of cells and organelles.

Prokaryotic Cell A cell that does not have a
membrane around its nuclear region; for
example, a bacterium.

Protein A molecule made up of a number of amino
acids arranged in a specific order determined by
the genetic code. Proteins are essential for all
life processes.

Receptor A specialized molecule of a cell’s

membrane that receives information from the
environment and conveys it to other parts of the
cell. The information is transmitted in the form
of a specific chemical that must fit the receptor
like a key in a lock.

Recombinant DNA Technology A body of tech-
niques for cutting apart and splicing together
different pieces of DINA. When segments of
foreign DNA are transferred into another cell or
organism, the substance for which they code
may be produced along with substances coded
for by the native genetic material of the cell or
organism. Thus, these cells become “factories”
for the production of the protein coded for by
the inserted DINA.

Replication The duplication of hereditary
material prior to cell division.

Respiration Within cells, the breakdown of food

molecules to liberate metabolieally useful energy.

Ribosome An organelle that contains RNA and
protein, and is the site of protein synthesis.

RNA ( ribonucleic acid ) A single-stranded nucleic
acid that contains the sugar ribose. There are
several forms of RNA, including messenger
RNA, transfer RNA, and ribosomal RNA (all
involved in protein synthesis), as well as several
small RNA’s whose functions are still being clar-
ified. Certain viruses have RNA, instead of
DNA, as their genetic material.

Second Messenger System A multi-step signal
amplification process used by the cell to
transmit, for example, signals from many
hormones that cannot enter the cell directly.

Steroid A molecule related to cholesterol. Many
important hormones, such as estrogen and
testosterone, are steroids.

Transcription The transfer of information from var-
ious parts of the DNA molecule to new strands of
messenger RNA, which then carry this informa-
tion from the nucleus to the cytoplasm.

Translation The conversion of the genetic instruc-
tions for a protein from nucleotides of
messenger RINA into amino acids.

Vesicle A small, membrane-bound, spherical sac in
the cytoplasm of a eukaryotic cell.

Page 5 — Based on a figure in Curtis, H., Biology (4th edition). Worth Publishers, New York, 1983.

55

Pages 6, 8 — National Library of Medicine, NIH.

Page 10 — (upper left) National Institute of Diabetes and Digestive and Kidney Diseases, NIH; (lower right)
Palade, G., University of California, San Diego.

Pages 15, 21 — Based on figures in Darnell, J., Lodish, H., and Baltimore, D., Molecular Cell Biology.
Scientific American Books, Inc., New York, 1986.

Pages 22, 23 (bottom) — Yunis, J.J., Human Pathology 12:494. W.B. Saunders Company, Philadelphia, 1981.

Pages 23, 26, 27 — Watson, J.D., Tooze, J., and Kurtz, D.T. , Recombinant DNA: A Short Course. W.H.
Freeman and Company, New York, 1983.

Pages 29 (top), 30, 32, 37, 46 — Friend, D.S., Brigham and Women’s Hospital.

Pages 29 (bottom two), 31, 38 — Based on figures in Luciano, D.S., Vander, A.J., and Sherman, J.H.,
Human Anatomy and Physiology (2nd edition). McGraw-Hill Book Company, New York, 1983.

Pages 34, 45, 47, 49 — Based on figures in Alberts, B., Bray, D., Lewis, J., Raff, M., Roberts, K., and
Watson, J.D., Molecular Biology of the Cell. Garland Publishing, Inc., New York, 1983.

Page 40 — Fujiwara, K., National Cardiovascular Center Research Institute, Suita City, Osaka, Japan.

Page 42 — Based on a figure in The Washington Post, December 28, 1986.

Illustrations on cover and on pages 5, 15, 18, 19, 21, 29, 31, 34, 38, 42, 45, 47, and 49 were
originally drawn by Trudy Nicholson. Some have been modified by Rick Myerchalk.

56

The New Human Genetics:

How Gene Splicing Helps Researchers Fight Inherited Disease

(NIH Pub. No. 84-662)

The Structures of Life:

Discovering the Molecular Shapes that Determine Health or Disease

(NIH Pub. No. 91-2778)

Medicines by Design:

The Biological Revolution in Pharmacology

(NIH Pub. No. 93-474)

Why Do Basic Research?

(NIH Pub. No. 95-660)

* U S GOVERNMENT PRINTING OFFICE: 1997

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