Sex and The Origins of Death

Sex and the
Origins of Death
This page intentionally left blank
Sex and the
Origins of Death
William R. Clark
OXFORD UNIVERSITY PRESS
New York Oxford

Oxford University Press
Oxford New York
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Copyright © 1996 by Oxford University Press, Inc.

Illustrations by Celine Park
First published by Oxford University Press, Inc., 1996
First issued as an Oxford University Press paperback, 1998
Oxford is a registered trademark of Oxford University Press
All rights reserved. No part of this publication may be reproduced,
stored in a retrieval system, or transmitted, in any form or by any means,
electronic, mechanical, photocopying, recording, or otherwise,
without the prior permission of Oxford University Press.
Library of Congress Cataloging-in-Publication Data

Clark, William R., 1938-
Sex and the origins of death / by William R. Clark.
p. cm. ISBN 0-19-510644-X
ISBN 0-19-512119-8 (Pbk.)
1. Cell death. 2. Death (Biology) 3. Apoptosis. 4. Sex (Biology) I. Title.
QH671.C56 1996
574.87'65—dc20 96-11753
10 9 8 7 6 5 4 3 2
Printed in the United States of America
Acknowledgments
A number of people have worked hard to help me

in various stages of creating this book. At Oxford University
Press I have enjoyed the continued encouragement and sup-
port of Kirk Jensen and Laura Brown. I am especially in-
debted to Joy Johannson, whose mastery of literary English
has been an inspiration and a guide. She pushed me to make
this a much better work than it might otherwise have been,
and greatly increased my pleasure in what I have written. In
this as in previous works I have found the advice of my good
friend and fellow scientist Robert Eisenstein of immeasur-
able value.
Contents
Prologue, ix
1. Death of a Cell, 3
2. A Second Face of Death, 27
3. Sex, Segregation, and the Origins
of Cellular Death, 53
4. From Sex to Death: The Puzzle
of Senescence, 79
5. A Hierarchy of Cells: The Definition of
Brain Death, 105
6. Standing at the Abyss: Viruses, Spores
and the Meaning of Life, 135
7. Coming to Closure, 159
Epilogue, 171
Further Reading, 181
Index, 187
Prologue
As promised so clearly and unapologetically in the

book of Genesis, knowledge carries with it a terrible burden.
Human beings, uniquely among all living creatures on this
earth, know that one day they will die. It is a painful knowl-
edge. We have spent most of our history as a knowing species
devising belief systems that help us either accept or deny that
single fact. No human culture ignores it. It colors our expe-
rience as individuals, and often influences our collective ac-
tions. Death is a subject that simultaneously terrifies us and
fascinates us. Understanding that terror and fascination is an
important part of human psychology.
While we continue to think about death from philo-
sophical, cultural or religious points of view, we also study it
scientifically. Thanatology, the study of death and dying, is
a recognized branch of medicine, with its own scientific
IX
PROLOGUE
journals. But thanatology focuses on the psychosocial aspects

of death and dying; it does not ask questions about the na-
ture of death itself. The branch of medicine called patholo-
gy describes in great detail the changes in the body and its
cells and tissues that lead to or accompany disease and death.
A pathologist can tell us whether a tissue is healthy or dis-
eased, alive or dead. But about the precise nature of the
razor-thin line separating life from death, the pathologist has
little to say.
So what is death! One way to understand the death of a
human being is to seek the smallest, ultimately indivisible
unit — the "atom" of the ancient Greeks — of human life.
That unit, that atom of life, is the cell. The cell is the small-
est unit in the human body of which we can say, "This is
alive!" And if we can define cells as having life, then it fol-
lows that it must be possible to describe them in the absence
of life—when they are dead. What does a dead cell look
like? What is it missing? Why is it dead? How did it make
the transition from alive to dead? How did it die ?
These are important questions, because the death of
every human being begins with the death of just a few cells.
We normally think of death in terms of death of the person—
the integrated whole composed of personality, will, memo-
ry, passion, and the hundreds of other things that make each
of us unique. Most of these characteristics are housed in a
specific portion of the brain — the cortex—and the loss of
"personhood" that results from loss of cortical function is
PROLOGUE
increasingly viewed as one of the most important aspects of

human death. But clearly death must also have a biological
meaning independent of the human condition. In the death
of our cells, we are no different from all of the other organ-
isms on earth condemned to die as a condition of birth.
Snails die, as do worms and mushrooms, and their deaths
too begin with the death of just a few cells.
The study of death at the level of individual cells has re-
vealed unexpected subtleties and complexities about the na-
ture of death in multicellular creatures like ourselves — for
example, the widespread occurrence of suicide among cells
in our bodies. Surprisingly, the study of evolutionarily older
single-cell organisms suggests that cell aging and death is not
an obligatory attribute of life on earth. Obligatory death as
a result of senescence—natural aging—may not have come
into existence for more than a billion years after life first ap-
peared. This form of programmed death seems to have arisen
at about the same time that cells began experimenting with
sex in connection with reproduction. It may have been the
ultimate loss of innocence.
Trying to grasp the meaning of an infinite and ever-ex-
panding universe has led toward an enormous abyss in
human understanding. From the edge of that abyss, we peer
anxiously through our telescopes into the fog of the un-
knowable. If we travel in the other direction—if we turn in-
ward and, with a succession of ever more powerful micro-
scopes trace the process of death down through the level of
XI
PROLOGUE
individual cells and into the molecules and atoms of which

they are composed — we come once more to a fog-filled
abyss, one that separates the phenomenon we call life from
the cold and indifferent physical universe. And we see
through our microscope a figure, peering anxiously at us
through a telescope. . . . Death brings us full circle.
XII
Sex and the
Origins of Death
1
Death of a Cell
If you know not how to die, do not trouble yourself. Nature

will in a moment fully and sufficiently instruct you. She will
do it precisely right for you; do not worry about it.
—Montaigne
The average adult human being is composed of

something more than a hundred trillion—1014—individ-
ual cells, each with a life of its own. The death of a human
being is a direct, irreducible consequence of the death of his
or her component cells. But what does death mean at the
level of a single cell? And how many of our cells have to be
dead before we are dead? In a complex multicellular organ-
ism like a human being, are some cells more important for
3
SEX AND THE O R I G I N S OF DEATH
being alive than others? What do we really know about these

elusive "atoms of life"?
In fact we know a great deal about the cells that make up
our bodies. We know, first of all, that life on earth certainly
did not begin in the form of multicellular animals like us.
The earth itself came into existence around five billion years
ago. The initial atmosphere created by gases escaping from
this newly condensed mass was very different from the air
we breathe today, and the materials dissolved in the newly
formed seas were also very different. The seas contained car-
bon- and nitrogen-based compounds which could be readi-
ly converted, under the influence of the tremendous ther-
mal, electrical, and radioactive energies raging over the earth's
early surface, into the basic building blocks of life, such as
proteins and nucleic acids. These reactions have actually
been reproduced in the laboratory, and the scenarios for ex-
plaining how these basic building materials arose are quite
believable.
Somewhere around four billion years ago, the very first
cells seem to have arisen from this inanimate matter, by
processes that today can only be guessed at. The guesses
made so far are not very convincing. These early cells did not
assemble themselves into multicellular animals for at least
two billion years after their first appearance on earth. In the
beginning life consisted of nothing more than single, free-
living cells. Yet whatever properties we may ascribe to life—
the ability to eat, to move about, to produce offspring—
were displayed by these single cells. Such organisms still exist
4
DEATH OF A CELL
today as bacteria, yeast, amoebae, and many other single-cell

life forms. Like their forebears billions of years ago, these
cells are tough. They have to be. Single cells are extremely
small, and now as in the beginning each cell has to survive
entirely on its own. Ultraviolet rays from the sun, as well as
the oxygen in the atmosphere, pose a constant threat to the
very material they are made of. The world around them is
dangerous and in a constant state of flux, changing almost
hourly. Temperatures shift; food and water sources come and
go; the acidity and salt level of their surroundings can wan-
der all over the map, passing in and out of the narrow range
able to support life.
The first cells to appear on earth arose directly from ma-
terials contained in the "primordial soup" — the collection
of bioorganic molecules generated in the high-energy reac-
tions mentioned above. As far as we know, these conditions
for producing cells from inanimate matter no longer exist on
earth. Cells, whether they are single individuals or part of a
multicellular organism, now arise only from other cells.
Every human life begins as a single cell, formed by the union
of a sperm and an ovum; approximately fifty rounds of cell
division are required to produce a fully formed person, by
which time the various daughter cells look as different as
brain and bone, or heart and bladder. Yet each cell, despite
outer appearances, actually differs from every other cell in
the body in only the subtlest ways. Each is the end-product
of billions of years of evolution, of natures practice in "get-
ting it right." And each of these near-perfect cells—with one
5
SEX AND THE ORIGINS OF DEATH
exception — must die. We will discuss this exception a bit

later.
The idea that plants and animals are made up of indi-
vidual cells that correspond to and are ultimately derived (in
an evolutionary sense) from the free-living, single-cell mi-
croorganisms that still permeate our environment was in-
spired by the use of increasingly powerful microscopes. The
first descriptions of free-living cells like yeast and bacteria,
or the amoebae found in freshwater ponds, began to appear
in the mid-1600s. They were referred to as "animalcules," or
little animals, in recognition of their status as living things.
At the time, no one had the slightest idea what cells were, or
of their significance as living things or as parts of living
things. The notion that the cells that make up plants and an-
imals might also be individual, self-replicating life units took
two hundred years to develop, and was not firmly established
until the late 1830s, when Theodor Schwann and Matthias
Schleiden proposed the "Cell Theory."
With the increasing perfection of the microscope, and
especially with the development in the latter half of the nine-
teenth century of chemical stains that could make the dif-
ferent parts of cells and tissues stand out from one another
in sharper contrast, it was gradually realized that the cells
making up a tissue have a sophisticated internal architecture,
and that this architecture can be related in precise ways to
the functions of the cell. The first subcellular structure to be
described was the nucleus, which because of its large size had
actually been discovered in the 1830s, well before the advent
6
DEATH OF A CELL
of staining techniques. Identification at the structural level

of other parts of the cell took longer, and association of struc-
tures with cellular functions only seriously got under way
after the development of the electron microscope in the
1930s and 1940s. The major working parts of the cell, called
organelles, were still being defined into the 1980s. Even today
there remain a few structures within the cell about whose
functions we are not entirely certain.
Cells are the smallest living units making up our bodies.
They are incredibly tiny; ten thousand of them clustered to-
gether are just visible to the unaided eye. Yet every cell con-
tains within it, in the form of a molecule called DNA, a kind
of chemical hologram of an entire human being. Each cell,
at least theoretically, has the information necessary to repro-
duce the entire being of which it is but the hundred-tril-
lionth part. This has actually been done in the laboratory in
a limited way with frogs, and the idea of doing it in humans
(and dinosaurs!) has generated more than one science fiction
novel. As a practical way of making human beings, however,
DNA "transplants" are a long way from becoming a threat to
our present means of reproduction.
Most cells in our bodies are born — and will live and
die—in complete and utter darkness. The vast majority of
cells within our bodies have never seen the light of day.
Unless they have managed to get in the way of an X-ray
beam, none has ever felt the sting of a photon on its surface.
Even the living cells of the skin, buried as they are beneath
layers of dead cells, have only a minimal sense of the light,
7
unless we insist on lying under the sun for hours on end

without protection. The one exception is cells of the retina
that line the back of the eye and gather light from the sun or
other stars, or from man-made sources. But this thin cell
layer is walled off from the rest of the body by an underlying
layer of connective tissue so dense and shiny in some animals
that it bounces photons right back through the retina a sec-
ond time, doubling their rate of capture (a useful trick for
night vision). Any photons managing to pass through this
connective tissue barrier beneath the retina run into a bone
wall — the thick, curving eye socket of the skull. The brain
is as much in the dark as any other part of the body.
When life began on earth, cells did not live in darkness,
unless they happened to be under a rock or at the bottom
of the sea. They certainly did not live buried in a mass of
other cells, creating their own darkness. When at last a few
cells came together to form multicellular organisms, they
unquestionably gained a great deal in terms of security. The
inner darkness that comes from being a small part of a large
biomass is a great way to escape damage from the sun.
Internal environments, particularly in mammals like us, are
relatively stable with respect to most of the parameters that
sustain life.
But there is a downside to this improved standard of liv-
ing. Cells that united to become multicellular also became
soft. Once they accustomed themselves to their new envi-
ronment and a life of relative ease, cells lost their toughness,
their ability to cope with conditions less than ideal. As a
8
DEATH OF A CELL
result, human cells are more vulnerable to threats from the

environment than are most single-cell organisms. There is a
concept in biology and medicine called homeostasis, which
refers to the delicate physiological balancing act that organ-
isms must perform within the range of temperature, acidity,
salinity, oxygen pressure, and other variables necessary for
life, and to the ability to control that range in one's environ-
ment. The permissible homeostatic range is much narrower
in animal cells than in their free-living, single-cell ancestors.
Moreover, as fixed parts of a multicellular organism, most
have lost their ability to move around if the supply of food
or oxygen runs low. They rely on things being brought to
them, and on their wastes being carried away for them.
Not only is it dark inside the body; it is also wet. All of
our cells are bathed in a gentle, never-ending stream of fluid
referred to as interstitial fluid or lymph. The sources of this
stream are the many branches of nearby arteries that bring
blood, with its life-giving oxygen and food substances, to
every cubic millimeter of the body. Each of these branches
keeps subdividing into ever-smaller arteries and arterioles,
eventually breaking up into tiny capillaries, microscopic ves-
sels from which oxygen and nutrients diffuse into the sur-
rounding tissue spaces, and from which small amounts of
lymph escape to help bathe nearby cells.
In order to understand how cells die, we have to know a
little about how they live. We will concern ourselves here
with only the broadest outlines of cell structure and func-
tion. Imagine for a moment that we are actually inside a liv-
9
ing cell — let's say a myocardial cell, one of the oblong cells
making up the muscular pumping walls of the heart. We will
have to bring along some rather powerful lights to see any-
thing inside this cell. We and the lights will also have to be
able to work under water — all cells are completely filled
with, as well as bathed in, fluid.
Myocardial cells, like many other cells in the body, have
their own highly specialized function. Their job is to con-
tract in coordination with one another so as to force blood
into the body's circulatory system. Inside each myocardial
cell is a set of protein sheets with enormous contractile
power. These sheets are anchored like bungee cords to each
end of the cell, and occupy over half of its free space. All the
myocardial cells making up the heart are under the control
of the heart s own built-in pacemaker, the sinoatrial node.
Sixty or seventy times a minute this pacemaker, assisted by a
"booster" — the atrioventricular node— sends out a wave of
electrical excitation that passes through the individual my-
ocardial cells making up the wall of the heart. For a brief in-
stant, each of these cells contracts its special protein sheets
and shortens to a fraction of its normal length. The force of
large blocks of cells contracting at the same time causes a
contraction of heart muscle, allowing the heart to pump
blood throughout the body.
As in most cells, the interior of myocardial cells is dom-
inated by a large, walled-off compartment called the nucle-
us. If you look carefully, you will see what appear to be little
round portholes all over its surface. These are where mole-
1O
Iff
Figure 1. Internal organization of a prototypical contractile cell. In this

model cell, a portion of the outer plasma membrane has been removed to
reveal the cell's interior. The large centrally disposed nucleus houses the cell's
DNA. The nucleus is characterized by distinct pores through which
molecules pass back and forth between the interior of the nucleus and the
cytoplasm. (The pores shown here are over-sized for illustrative purposes.)
Bands of contractile filaments stretch from one end of the cell to the other;
in a myocardial cell, these filaments would occupy up to seventy-five
percent of the cell's interior. Numerous mitochondria (M) are disposed
around the cytoplasm, many of them in intimate association with the
contractile fibers. The endoplasmic reticulum (ER) is a major site of protein
synthesis in the cell. Proteins are synthesized on ribosomes (R). An enlarged
example of ribosomes bound to a strand of messenger RNA (copied from
DNA in the nucleus and sent to the cytoplasm) is shown floating free in the
cytoplasm. Lysosomes (L) are sites for disposal of intracellular waste
products. The surface (plasma) membrane of the cell contains numerous
membrane pumps (MP).
cules are passed back and forth between the nucleus and the
rest of the cell. If cells themselves were to have a brain, the
nucleus might well be it. The nucleus houses the DNA, which
contains (in the form of genes) the blueprints for every sin-
gle characteristic of the cell and the instructions for operat-
ing all its machinery. Interestingly, only a few percent of the
total DNA in a cell is actually organized into the genes for
guiding a cell through life; the rest of the DNA has no dis-
cernible function or meaning, and has been labeled "non-
sense DNA."
The machinery for operating the cell is found in the liq-
uid cytoplasm filling the cell outside the nucleus. These hum-
ming oblong tanks over here are actually power generators
called mitochondria, which convert food and oxygen into the
universal currency of energy in living cells, known as ATP
(adenosine triphosphate). If we swing the light over here for a
moment, you can perhaps just make out these clusters of
slightly asymmetric dumbbell-shaped machines called ribo-
somes strung together by an almost invisible thread of mes-
senger RNA (mRNA). The mRNA is in effect a xeroxed set of in-
structions, copied from one of the genes in the DNA, that
directs the construction of a protein. The ribosomes operate
twenty-four hours a day, seven days a week, stamping out an
incredible variety of protein products. Some of the ribosomes
float freely in the cytoplasm; others are anchored to convo-
luted internal membrane structures called the endoplasmic
reticulum. Most of the proteins produced by the ribosomes
will be used by the cell to maintain itself, although some
12
DEATH OF A CELL
cells—the insulin-producing beta cells of the pancreas, for

instance — make proteins for export to other parts of the
body. Overhead you can see row upon row of those contrac-
tile protein sheets we were talking about earlier, the ones that
allow myocardial cells to carry out their special function in
heart-muscle contraction. Notice the clusters of mitochon-
dria snugged up next to them for efficient delivery of the
large amounts of ATP needed to carry out their repetitive con-
tractions. Be careful—you don't want to fall into one of
these structures right over here: they are the lysosomes, where
all the trash is disposed of. Anything put into a lysosome is
rapidly degraded into a soupy mush by powerful chemical
agents and potent enzymes.
Finally, as we make our way toward the outer limits of
the cell, we will encounter—put your hands out, right over
here; you can feel it—the soft, spongy boundary of the cell,
the plasma membrane. It is made mostly of fat and choles-
terol, to keep the watery interior of the cell completely sep-
arate from the fluid environment outside the cell. But the
plasma membrane is much more than just a barrier. These
bumps located every few microns along the wall are actually
powerful pumps. Cells depend on these pumps in the same
way that reclaimed land near the ocean's edge depends on sea
pumps. The environment within a cell is very different from
the environment outside. The cytoplasm is jammed full of
the special chemicals, proteins and salts the cell needs to sus-
tain life. And the concentration of these molecules inside
cells is often much higher than the concentration outside.
13
Conversely, the concentration of water outside the cell is

much higher than the concentration of water inside. As a re-
sult, there is a constant tendency for water to rush into cells
under osmotic pressure. It is the task of one set of membrane
pumps to pump this water back out as soon as it enters. This
involves an enormous expense of biological energy, but if it
is not done quickly and efficiently the cells will swell and
burst. Cells also maintain much lower levels of sodium and
calcium ions inside than are found in the surrounding flu-
ids, and much higher levels of potassium ions. Cells use sep-
arate sets of energy-driven pumps to maintain these ionic
gradients. If any of the pumps shut down, the cell will quick-
ly die. The coordinated activity of these pumps is absolutely
vital to the life of the cell.
We can't see them from here, but on the outside of the
plasma membrane are all the lifelines the cell uses to stay in
touch with other cells. Some of these are simply mailboxes
into which other cells deposit chemical messages that are
acted on as the cell thinks fit. There are special regions of the
cell surface that act essentially as Velcro patches, allowing
each cell to adhere tightly to its neighbors. And since we are
inside a myocardial cell, we would find just on the other side
of this membrane a series of insulated plates through which
the electrical impulses generated by the heart's pacemaker
reach the cell. Down at the other end of the cell is an iden-
tical set of plates where the wave passes through to the next
cell. When all is working as it should, sixty to eighty waves
pass unbroken through the cell each minute.
14
DEATH OF A CELL
Although it doesn't know it yet, the myocardial cell we

are in is about to die. It will die because of myocardial is-
chemia, or deprivation of blood supply to the portion of the
heart in which our cell lies. The first sign of danger, if our
cell could read such signs, is a gradual tapering of the stream
of lymph fluid flowing over its outer surface. The ultimate
source of this stream — one of the small arterial branches
bringing blood to this particular region of the heart—has
been gradually narrowing for several years now, like a tiny
brook clogged by rocks, tree branches, mud, and other de-
bris. In this case the debris is a complex mixture of fat, cho-
lesterol, and dead blood cells that has been building up in-
side the arterial wall for several years. This process began
when excess dietary fat and cholesterol in the blood were laid
down in what is known as a fatty streak, which attracted the
curiosity of white blood cells passing through the artery.
White cells are constantly on patrol in the bloodstream,
looking for anything that might pose a threat to the body.
Unable to clear this unwanted material out of the way, they
too ended up getting bogged down in the mess, dying and
adding to the logjam. As a result the normal healthy flow of
blood through the artery has slowed to a tiny stream over the
past several months, and the amount of lymph fluid that can
be released from downstream capillaries fed by this artery has
become vanishingly small.
The cell we are in has had no sense of any of this. But as
the supply of lymph bathing the surrounding heart muscle
begins to slow to the barest of trickles, and even shuts off in-
15
termittently, the cell senses that something is terribly wrong.

The decreased flow of lymph fluid means a decrease in the
supply of life-sustaining materials dissolved in it, in particu-
lar food and oxygen. The mitochondrial ATP generators, re-
sponsible for supplying energy to the entire cell, begin to
shut down all around for lack of fuel and oxygen. The
amount of ATP inside the cell begins to fall below the critical
level needed to maintain normal cell function. In response,
less efficient backup generators kick in and continue to hum
for awhile, burning emergency stores of intracellular food
like starch and fat, and even protein, in the struggle to keep
up with the demand for energy. But these stores will soon be
exhausted, and the auxiliary generators too will be forced to
shut down. Momentary metabolic stillness will be added to
the dark; in a matter of seconds the lack of ATP will start to
wreak havoc everywhere in the cell.
You can probably feel it starting to happen. Most criti-
cally affected by the lack of energy are the powerful pumps
operating in the plasma membrane at the outer reaches of
the cell, the ones that hold potassium in, and keep water and
calcium out. So crucial to the life of the cell are these pumps
that they are given absolute precedence for the ever-dimin-
ishing supply of ATP. It is no longer a question of function;
it is now a matter of survival or death. All other energy-dri-
ven operations in the cell, including contraction of the sheets
that drive the pumping function of the heart, are forced to
shut down to save fuel for the pumps. The protein-synthe-
sizing machinery stands everywhere idle in the cell; messages
16
DEATH OF A CELL
from the nucleus pile up unread. Partially finished products

of every description begin to drop off assembly lines as ATP-
dependent enzymes wait for new energy supplies to arrive.
Chaperones of the unfit and the incomplete rush to trans-
port them to disposal units. The lysosomes are driven to a
frenzy as they try to deal with all the trash being fed into
them. Everywhere the cry is the same: "Where is the ATP?"
But the ATP never comes; one by one the membrane
pumps sputter and lie still. Calcium slips in through the
gates that used to exclude it, and begins to corrode and dis-
tort the mitochondria bobbing silently in the dark. And then
water rushes in, torrents of it. The cell begins to swell,
putting unbearable pressure on the outer plasma membrane.
Finally this membrane, this wall that isolates and protects the
cell from the outside world, begins to crack; the cracks widen
with increasing speed until the membrane rips open and the
entire cell literally explodes into the outer darkness, spilling
its now-useless machinery and its very sap into the nearly dry
lymph stream trickling by outside.
These events do not go unnoticed by the rest of the
body. The body is a larger community of cells, and like every
organized community, it has individuals who specialize in
dealing with the dead. White blood cells are constantly on
patrol in the body, drifting quietly through the blood and
lymph. Some are armed to the teeth, on the lookout for in-
vaders that can cause disease and death. But these warrior
cells do not always prevail, and even when they do diere may
be incredible carnage, with as many dead white cells as dead
17
invaders. So wherever they go, the warrior cells are accom-

panied by a corps of undertakers called macrophages, white
cells that may participate in the battle, but who are also
trained to take care of the dead. The inner parts of cells float-
ing by in the lymph fluid alert the macrophages to the pres-
ence of death, and they begin trudging upstream, working
their way through the ever-increasing density of floating de-
bris until they arrive at the source. These dealers in the dead
glide silently through the area, probing, testing, sliding on
past those with a firm belly, looking for the flabby, waving
fragments of membrane that identify the corpses. The
blocked artery has resulted in the death of not just one cell,
but thousands. There will be much to do.
The macrophages set about quickly and efficiently re-
moving the dead. They do not embalm them, nor do they
bury them. They eat them, which is how they came by their
name — macrophage means literally "great eater" in Greek.
They embrace the remaining fragments of dead cells and
sweep them inside into their own lysosomes where they are
quickly degraded into their component parts, which will
eventually be released back into the bloodstream to be used
as nutrients by other cells. Thus are the dead recycled inside
the body, just as one day the body itself will be recycled in its
entirety, through soil and through plants, to provide nutri-
ents and oxygen to nourish human cells yet unborn. The
macrophages work silently at their task, recruiting nearby
worker cells called fibroblasts to help them wall off the area
18
DEATH OF A CELL
of death with thick layers of pale scar tissue. When all is fin-
ished the macrophages will slip away into the lymph to re-
join their warrior brothers, leaving behind a scene bereft of
life, as cold and as still and as white as the surface of the
moon.
The cell we just watched die is part of a heart, and the heart
belongs to a human being—in this case, a man, sixty-two
years old. This heart has beat faithfully in his chest over two
billion times, sending life-giving blood out to the cells and
tissues in his body. But he now lies pale and limp on the hall-
way floor of his home; he has suffered a major heart attack.
It is not his first. His initial heart attack, two years earlier, in-
volved ischemia to a significant portion of heart muscle that
subsequently became infarcted— converted into dead, func-
tionless myocardium overridden with whitish scar tissue.
The pumping efficiency of his heart was reduced consider-
ably, but he was left with enough residual function to lead a
fairly normal life. This second attack involves blockage of a
different artery, but one that also serves the musculature of
the critical left-ventricular heart chamber, which carries the
major burden of pumping blood from the heart out into the
rest of the body.
He awoke at six o'clock this morning as usual. He sat
up in bed and put on his slippers, stood up, yawned and
stretched, and headed out of the bedroom to bring in the
morning paper. He had just turned the corner into the hall-
19
way when he was literally brought to his knees by a horren-

dous crushing chest pain. There was no doubt at all in his
mind what it was; it was like the first attack, but much,
much worse. Within seconds he lost consciousness and col-
lapsed the rest of the way to the floor. Like the majority of
heart attacks, his came early in the morning, at a time of rel-
ative inactivity and low demand on the heart itself.
His wife also knew, within seconds of hearing him cry
out and bump against the wall, what had happened. She
would recall later that the blood seemed to drain from her
completely for a moment, leaving her terrified and helpless.
But then, her own heart beating wildly, she took a deep
breath, rose quickly from the bed and went out into the hall-
way. She had tried to prepare herself for this possibility after
he had his first heart attack. Warned by their doctor that it
might very well happen again, she had taken a course in CPR
(cardiopulmonary resuscitation) at a nearby fire station.
Now it is here; now it is real. Pushing panic into the
background, she kneels beside him on the floor. He is sweat-
ing profusely, his eyes closed. She calls his name, shaking him
and slapping his cheeks. He does not respond; he is uncon-
scious. She checks his neck for a pulse and feels none. She
knows this is not good, but not necessarily hopeless. She
moves quickly to the phone and dials 911. Her voice is shak-
ing and she is incoherent at first. The dispatcher works her
calmly through the necessary information. Learning that she
is familiar with CPR, he urges her to begin immediately. Help
is already on the way.
2O
DEATH OF A CELL
She struggles to turn her husband over on his back. She

cannot detect breathing; there is no rise and fall of his chest,
and when she tilts his head back and opens his mouth, she
can feel no breath on her cheek. She immediately gives him
two of her own lungsful of air in mouth-to-mouth respira-
tion. She moves over him and feels for the tip of his ster-
num— nearly two minutes have now passed since she heard
him fall. She begins a series of rhythmic, rapid downward
thrusts with the heel of her palm, three finger widths above
the tip of his sternum, to push the blood out of his heart and
into the arteries. Alternately with these compressions she
forces air into his lungs with her own breath. She keeps re-
peating this cycle — fifteen compressions, two breaths —
until the first-response team arrives four minutes later.
As in most communities, the first-response team is an
engine company with firemen trained in basic life-support
techniques. Two of the firemen take over administration of
CPR, while a third hooks up a heart monitor to the man's
chest and a fourth leads his wife into the living room, where
he tries to calm and reassure her, and to gather basic infor-
mation about her husband's health. A rapid assessment of
cardiac function indicates that the man is in ventricular
fibrillation. Electrical signals emanating from the sinoatrial
node are coursing throughout the heart in a completely un-
coordinated fashion, trying to get the muscles to contract
and pump blood. The combination of previously weakened
heart muscle and the damage from the current attack has
caused his heart to contract spasmodically, in different places
21
at different times, without the integration needed for effec-

tive pumping. As a result, there is no regular pulse or recog-
nizable pattern of spiking on the ECG (electrocardiogram)
monitor now attached to his chest. The blood flow from his
heart to the rest of his body has dropped to a mere fraction
of normal.
Virtually all first-response teams are now equipped with
a portable electric defibrillator. Experience of the past ten
years has shown that for patients in ventricular fibrillation,
immediate electrical defibrillation, before administering
drugs or any other resuscitative measure, is the most impor-
tant parameter for saving lives. It has been nearly eight min-
utes since the beginning of his attack. Paddles are pressed
firmly onto saline-soaked gauze pads placed over each side
of his chest—one just to the right of his sternum, the other
just to the left of his left nipple. A terse command is given
and everyone steps back. The man arches in a powerful
spasm as 50,000 watts of power surge briefly through his
thorax, and then he sinks back to the floor. The purpose of
so much electrical power is not to "jump-start" his heart but
rather to shut it down completely; when it restarts on its
own, there is a good chance the sinoatrial and atrioventricu-
lar nodes will be able to reestablish a coordinated cardiac
rhythm.
But a glance at the monitor shows the same erratic pat-
tern as before. The defribrillator, its paddles serving as elec-
trodes to the man's body, analyzes the heart rhythm and the
22
DEATH OF A CELL
resistance of the chest cavity to the electrical shock just given,

and adjusts output automatically if further shocks are indi-
cated. They are. After the command to stand clear is given
once again, current is quickly applied a second time, and
then a third, before somediing approximating a normal heart
rhythm begins to appear. The defibrillator screen flashes a
message that no further shocks are needed. One of the fire-
men keeps an eye on the monitor while another continues to
blow through a mouth tube into the man's lungs; he is still
not able to breathe normally on his own.
By now the advanced cardiac life support (ACLS) unit has
arrived. It is twelve minutes since the attack began. They
walk straight through the door purposely left open for them;
the fireman in the living room nods toward the hallway. The
ACLS paramedics take over smoothly from the firemen. One
keeps an eye on the monitor while a second probes and pats
the man's veins to find one suitable for an i.v. (intravenous)
needle. A third begins to slide a long, slightly curved tube
down the man's throat. Manual CPR and defibrillation have
failed to restart a normal breathing pattern. It is difficult to
get the tube placed properly; although unconscious, the man
is gagging and has vomited. Fortunately there is little in his
stomach, but it is still hard to get the tube inserted. The para-
medic wants to place the tube into the trachea in order to de-
liver air directly to the lungs. The attempt is interrupted
while one of the paramedics uses a balloon pump to force
more oxygen into the man's lungs. The intubation requires
23
at least two additional minutes to complete. Finally the tube

is properly placed, and the paramedic begins pumping large
quantities of pure oxygen rhythmically into and out of the
man's lungs. Fifteen minutes have now elapsed.
At last the man picks up the breathing rhythm on his
own. His heart pattern appears to be stable. The ACLS para-
medics administer drugs through the i.v. line started earlier,
to help stabilize him for the ride to the hospital. The breath-
ing tube is left in place; all the other equipment is cleared
away. He is lifted onto a gurney, and quickly wheeled to the
ambulance. The emergency equipment is thrown into the
back, and the ambulance sets off, siren screaming in the still
morning air. A neighbor follows in a car with the man's wife.
From a telephone inside the speeding ambulance the para-
medic in charge describes the situation to the hospital so that
staff will be ready when they arrive.
Many questions remain, and they can only be answered
by coronary critical-care specialists who will perform the
necessary evaluative and laboratory tests at the hospital.
Unquestionably, had he not received immediate CPR fol-
lowed by defibrillation and intubation, their patient would
have been dead many minutes ago. But he is still uncon-
scious, which worries the paramedics. And he was not
breathing properly when they arrived at the house. Did he
manage in spite of his trauma and breathing difficulties to
get enough oxygen to his brain cells to prevent irreversible
brain damage? How much cardiac damage — infarction of
24
DEATH OF A CELL
heart muscle—has this morning's attack inflicted? Will his

heart be able to withstand much longer the cumulative de-
struction of two major attacks?
We will rejoin our patient a little later, once he has
reached the hospital. He will be subjected to further emer-
gency procedures to stabilize his condition, and then exam-
ined by specialists to determine the precise extent of the
damage. In the meantime, let us examine death a bit more
closely, for it is a possible outcome of our story.
25
2
A Second Face of Death
Let us therefor consider howfarre and in how many waies

selfe-homicide may bee allowable.
—-John Donne
The death of a myocardial cell described in the last

chapter—caused by starvation, and by suffocation from lack
of oxygen—was an ugly death: violent, chaotic, disorderly.
That kind of death happens as a result of accident or mis-
chance, and is called necrosis. It is the way death comes to
fragile cells inside the body when the delicately balanced
conditions for maintaining life veer too far off center. It is
also the way cells die when they are poisoned, for example by
27
one of the many toxins released by bacteria and other path-

ogenic microorganisms. Necrotic cell death is usually ac-
companied by wholesale destruction of the internal parts of
the cell, by the gushing in of extracellular water and the rip-
ping open of the cell membrane. The macrophages that
come in to clean up the dead and dying cells trigger the de-
position of scar tissue that makes it difficult for healthy cells
to move into the damaged area and replace lost cellular func-
tions. Scar tissue is a useful response to damage in many
parts of the body; it promotes healing and keeps tissue from
losing its shape. But it cannot help a heart beat or a brain
think.
For many years, this form of cell death was thought
to be the way all cells came to an end. In fact, no one paid
much attention to how cells died. Perhaps understandably,
biologists mostly have been fascinated with how cells live,
how they function, how they reproduce themselves. But cell
death can be equally complex and fascinating. It turns out
that there is another way entirely in which cells die, a way
that is very different from necrosis. It is not a result of acci-
dent or mischance; it is programmed into cells and is acti-
vated only under very special conditions. Its discovery led to
the creation of a whole new field of inquiry, and now the
study of programmed cell death is one of the leading topics of
molecular biology and medicine.
To examine this second face of cell death, let us enter for
awhile the world of a human fetus developing in the womb.
This would seem an unlikely place to seek death, this very
28
A SECOND FACE OF DEATH
temple of life and growth and increase. Yet here, too, death
plays a role — an important role, one absolutely vital to the
creation of a complex new being. One of the instances in
which this can be seen most readily is in the genesis of the
human hand.
In the first eight weeks of life, human embryos undergo
almost uninterrupted cell growth. This is the period during
which the plan for the entire body, including all the major
internal-organ systems, is laid down. By the end of the eighth
week a human embryo is clearly recognizable as human, and
it graduates to the status of fetus. The limbs of a human
fetus—the future arms and legs with their appended hands
and feet — make their first appearance during the period of
embryonic growth, at the end of the fourth week of life.
They begin as small bumps on the margin of the evolving
body structure, pushing out rapidly over the next several
weeks to achieve their final form. The future arms are always
a few steps ahead of the future legs. By the end of the sixth
week of development, the three major segments of the arm
are clearly visible: the upper arm, the forearm, and the hand.
The hand at this stage looks more like a ping-pong pad-
dle than a tool that will one day hold a pen or a violin bow.
Traces of future finger bones are just barely discernible as
faint lines of condensing cartilage connected by webs of tis-
sue. This is a characteristic stage in the development of all
vertebrate animals, and is an example of the embryological
principle laid down by the biologist Ernst Haeckel in the last
century: ontogeny recapitulates phylogeny (the history of an in-
29
Figure 2. Development of the human hand. The human foreiimb first
appears as a tiny swelling along the trunk of the fetus at the end of the
fourth week of development. By the fifth week the foreiimb (fl) has begun
to push out (top figure and a), and the hindlimb (hi) bud has appeared (top
figure). At the end of the fifth week the foreiimb is a simple paddlelike
structure (b). At six and a half weeks (b), the cartilage that will give rise to
the bones of the hand and fingers begins to condense, but the future fingers
are still connected by a webbing of cells (c). By two months (d), the hand is
fully formed; the fingers even have tiny nails.
dividual fetus in the womb recapitulates the biological his-

tory of that fetus' ancestors). Although stated somewhat
overambitiously by Haeckel, the principle has a certain va-
lidity. All vertebrate embryos, for example, pass through a
stage where they have gill structures in the neck region. Fish
keep these gill structures to help them breathe underwater as
adults. Human and other higher vertebrate embryos pass on
through this stage, using leftover gill tissue to fashion more
useful structures, like the thymus or the thyroid glands.
Similarly, all vertebrate embryos pass through a stage where
the digits of the hands and feet are webbed. Fish and some
birds maintain this webbing throughout life, reinforcing it
and using it in the construction of fins or wings or webbed
feet. In human embryos, between the forty-sixth and fifty-
second days in the womb, the interdigital webbing of the
hand suddenly disappears, leaving behind five beautifully
shaped fingers. Trailing along just a few days behind, the
same process is repeated to create a human foot complete
with toes.
It is strange that this process had been described in great
anatomical detail for a hundred years or so before anyone
bothered to ask what happens to the cells that make up the
interdigital webbing. It turns out that they do not just move
away to some other part of the body, or get incorporated into
the palm of the hand or the nearby wrist. They die. One by
one, over the course of a few days, each of the cells forming
die webbing between the fingers and toes of a human embryo
dies. But they do not die the raucous, violent death of necro-
31
sis. They do not die because their blood supply is interrupt-

ed or because water or deadly calcium seeps into them.They
act in response to a script embedded deep within them long
ago, over which they have no control. Responding on cue to
signals from their environment, they commit suicide.
The death of a cell by suicide is altogether different from
necrotic cell death. Necrotic cell death is cytocide, the killing
of a cell that does not want, and is not scheduled, to die. The
cell dies in response to changes outside itself, some lethal al-
teration in its immediate surroundings. As we have seen, a
cell dying of necrosis struggles violently, with everything at
its disposal, to avoid death. The act of suicide by a cell is
completely different. One cannot help being struck by how
peaceful a death it seems, and all in all a rather unmessy one.
Although it may involve large numbers of cells at a given lo-
cation, the cells do not explode as a result of osmotic imbal-
ance. There is no rushing in of water, or spillage of intracel-
lular debris into the surrounding tissue fluids, attracting the
eaters of the dead.
It would be easy to anthropomorphize the suicide we see
in cells, and we mustn't do that. Suicide by cells lacks com-
pletely one very important element of suicide as we com-
monly think of it: volition. Individual cells do not have any-
thing remotely approaching free will either in their lives or
in their deaths. When cells commit "suicide," they are re-
sponding to a program they cannot alter in any way. The im-
pulse to commit suicide ultimately does come from within,
32
but it is not in response to sorrow or despair, nor is it a form

of altruism. None of these exist in cells. What does exist, in
all cells — in every cell in our bodies—is a built-in program
for self-destruction, should the need arise. The number of
situations in which the need arises is surprisingly large.
One of the first events to occur in most cell suicides is a
subtle one, yet for a living cell it is as final and irreversible as
any act of self-destruction could be. As we have seen, the nu-
cleus of a cell is in a sense the nerve center of the cell. It con-
tains in its DNA the master plans for every protein the cell is
equipped to make, along with complex sets of instructions
for regulating their production at just the right time.
Virtually every aspect of a cell's life is regulated by its DNA,
including its death. Once a cell commits itself to death by
suicide, it copies off one last set of instructions from the DNA
in the nucleus and sends them to the machinery located out
in the cytoplasm. These are the instructions for the cell's own
death. As soon as they have been received and processed, the
cell begins to destroy all of the DNA in its nucleus. The DNA
is broken up into millions of tiny bits that can no longer
convey any useful instructions to the cell, in the same way
that this page, if torn into a thousand minute fragments,
could no longer be read. This does not happen because some
deadly destroyer of DNA has managed to penetrate the nu-
cleus; everything necessary to do the job is already in the nu-
cleus, waiting for just the right time, waiting for a signal to
set the process in motion. From the moment its DNA has
33
been destroyed, the cell cannot reverse course; it cannot alter

its decision. It may take awhile to become apparent, but the
cell is already dead.
The fact that its central command system has been de-
stroyed is not immediately noticed by the rest of the cell.
There is always a stack of instructions from the nucleus piled
up in the cytoplasm, waiting to be read, and the cell can con-
tinue to operate for quite some time after destruction of its
brain — of its DNA. It carries on for awhile clearing away the
backlog of work to be done, including processing of the
death messages. Its situation is somewhat analogous to that
of a human being who is brain-dead, but whose body, with
Figure 3. Death by apoptosis. The cell shown here was originally a simple
sphere, surrounded by a well-defined plasma membrane. It has now begun
to disintegrate into numerous smaller apoptotic bodies, each of which
contains a small portion of the interior of the previously intact cell.
Redrawn from an electron micrograph of a real cell undergoing
apoptotic death.
34
modest assistance, can continue to function more or less nor-

mally for weeks or even months. But as surely as a patient
who is brain-dead will never again be able to participate in
those functions we associate with human life, a cell whose
DNA has been destroyed is irreversibly, irrevocably dead.
If we were to view this process from outside the cell, we
would have no indication that the cell's DNA is gone, or that
anything is amiss. The first hint that something unusual is
underway involves the cell's plasma membrane. As a sign that
a given cell has somehow been singled out for a fate differ-
ent from its neighbors', the cell physically detaches itself
from them. One by one it breaks the points of contact be-
tween its own plasma membrane and the membranes of sur-
rounding cells, until it stands alone. And then the cell begins
a slow dance of death; its membrane begins undulating to
and fro, ruffling like the gossamer tissues of a Portugese
man-of-war propelling itself through water. Portions of the
plasma membrane surge out and then fold back on them-
selves. Small pieces of the cell begin to pinch away from the
main cell body, and float idly in the currents of the sur-
rounding lymph.
The anatomical events accompanying suicide in cells
were first described in detail by three Scottish scientists at the
University of Aberdeen in 1972. In consultation with a clas-
sics scholar at their university, they came up with a wonder-
fully appropriate name for it: apoptosis (ap'o-to'sis), a Greek
word that describes the falling away of petals from a flower,
or leaves from a tree. That is exactly what cell suicide looks
35
like when seen through a powerful electron microscope.

Portions of the cell, with various bits of the internal cell ma-
chinery— ribosomes, mitochondria, even lysosomes, still
surrounded by plasma membrane — fall gently away from
the main body of the cell. Inside these cell fragments, or
apoptotic bodies, as they are called, life seems to go on more
or less normally. Ribosomes, if they are included, continue
to make protein; entrapped mitochondria still churn out
ATP; pumps at the edges of the membrane still labor to push
excess water out of the cell. It is as if, at least for awhile, all
the systems trapped inside the apoptotic bodies are com-
pletely unaware that they have been partitioned off from the
main body of the cell.
The calm prevailing inside the apoptotic bodies is re-
flected in the surrounding tissue spaces. There are no out-
ward signs of death—no ruptured membranes, no chemicals
and debris from exploded cells washing downstream in the
lymph. There are no legions of white blood cells marching
into the area, looking for the killing fields. The apoptotic
bodies are eaten quietly and efficiently by neighboring cells,
not by professional undertakers. Of course, if a macrophage
happens by, it will join in and help speed the process along.
But the macrophage does not send out alarms to attract
more of its kind to the scene. Nor does it — and this is very
important — stimulate nearby fibroblasts to lay down scar
tissue. Areas of the body in which cell suicides have taken
place are not walled off or given up as dead and useless. Cells
disappearing by suicide leave behind only normal, healthy
36
tissues, bathed as always in nutrient- and oxygen-filled

lymph fluids.
Apoptotic bodies can actually be seen inside neighbor-
ing cells shortly after they have been eaten—still intact, still
blithely carrying on their business unaware that anything is
wrong. Only at the final moment, when they are shepherd-
ed into their new host's lysosomes for destruction, do they
seem to realize something is seriously wrong. But a brief in-
stant later it is all over, and they are started down the path-
way of decomposition and disassembly that will return them
to their elements—which of course will be used by the ac-
commodating host cell in pursuit of its own ends.
The death of cells by suicide is involved in a great deal
more than just the shaping of fingers from a webbed hand.
In the developing human fetus, cell suicide also plays a major
role in the formation of the nervous system. Nerve cells in
the brain and spinal cord (neurons) are connected to other
parts of the body by nerve fibers — long, thin extensions of
cells residing in the brain or spinal cord and carrying electri-
cal impulses that stimulate targeted cells to perform specific
functions. At a certain stage of fetal development, these neu-
rons begin generating enormous numbers of nerve fibers,
which they simply cast out in the general direction of tissues
and cells needing nerve connections. If a particular nerve
fiber happens to find a cell with a nerve attachment point
on its plasma membrane (a muscle cell, for example), it
makes a connection. That fiber (and the brain or spinal-cord
neuron from which it came) survives and becomes the ner-
37
vous systems communication line to the targeted cell for life.

If, on the other hand, the nerve fiber fails to establish con-
tact with an appropriate cell—and fewer than half do—the
neuron that sent it out must commit suicide, dying the same
quiet apoptotic death that helped to form the hand.
The role played by cell suicide in the genesis of the ner-
vous system represents an interesting and fundamental fact
about the biology of this kind of dying in many cells: death
is actually the default state for each of these neurons. From
the moment a neuron is spun out of the central nervous sys-
tem toward potential target cells, it is destined to die. Only
if it finds a connection with another cell will it be rescued
from an otherwise certain death; it will receive chemical sub-
stances (called growth factors) from the target cell that in ef-
fect switch off the death program. In some respects this
seems an incredibly wasteful way to build a nervous system.
Each nerve cell that fails to make a connection with anoth-
er cell in the body, and thus goes on to commit suicide, was
very expensive to make in terms of biological energy. As with
other tissue-shaping processes in which apoptosis plays a
role, the development of the nervous system probably re-
flects a phylogenetically earlier process that was more effi-
cient. Although now it may be considerably less efficient,
overall it must be less expensive and more practical to use the
inherited system at a lower efficiency than it would be to de-
sign a completely new way of building a nervous system
from scratch. So the brain and the spinal cord build millions
38
of cells they will never use, shunting the unselected into

death through suicide.
The process of suicide continues after birth and
throughout life. Cells of the immune system, including the
warrior cells we met earlier, are also generated in great excess.
These cells—white blood cells called lymphocytes—are al-
lowed to circulate throughout the body for several weeks
after they are formed. If they encounter a threat to the
body— a foreign protein in the bloodstream, or a virally
infected cell — and eliminate it during that time, they will
be granted longevity. As when neurons make contact with a
targeted cell, lymphocytes detecting a foreign protein or en-
gaging a virally infected cell are rewarded with growth fac-
tors that switch off their death program. The resulting cell
may survive five years, or ten, or even for the life span of its
host, providing a type of "memory" of pathogens previously
encountered by the immune system. But if they fail to find
and eliminate a foreign invader during the allotted trial pe-
riod, they are invited, in effect, to fall on their swords. Again,
death is the default state for these white blood cells. They un-
dergo exactly the same kind of death as cells in the webbing
that binds embryonic fingers together. The phenomena of
cellular overproduction, selection, suicide, and memory are
examples of the many ways in which the nervous system and
the immune system seem to parallel one another.
There is another interesting situation in which cells of
the immune system commit suicide: if they receive too much
39
radiation. This phenomenon has long intrigued and puzzled

both immunologists and radiation biologists. One charac-
teristic feature of the immune system is the tremendous
amount of cell division that is constantly going on in order
to satisfy the body's demands for fresh supplies of immune
cells. Part of this demand is of course created by the fact that
so many immune system cells end up committing suicide
when they fail to find anything foreign or abnormal to at-
tack. Cells that are constantly dividing are particularly sus-
ceptible to radiation damage; that is the basis of radiation
treatments for cancer. Radiation is dangerous because it can
introduce mutations into the DNA of cells that are dividing.
Mutations creeping into cells of the immune system can be
particularly dangerous, because they may cause the immune
system to attack normal, healthy cells as well as cells com-
promised by pathogens or cancer. This possibility preys on
one of the body's most deeply seated fears: the development
of abnormal DNA—DNA that is not self; DNA that could turn
against self. To avoid this risk, it seems that the immune sys-
tem chooses to rid itself of radiation-damaged cells, and
again, the preferred death in such situations is suicide.
Interestingly, most current treatments for cancer play on this
same fear. Both radiation therapy and chemotherapy act by
damaging a cell's DNA, ultimately causing tumor cells to un-
dergo apoptosis.
In discharging its duty to rid the body of intracellular
predators, the immune system also exploits the propensity of
other cells to commit suicide when their integrity is com-
4O
promised. This is the specific task of a highly specialized cell

called a "killer T cell" around the lab. (The more polite term
cytotoxic T lymphocyte or CTL is used in scientific papers and
grant applications.) CTLS are one type of the warrior white
blood cells we met earlier, the ones that patrol the body with
undertaker macrophages in tow. One of two major arms of
the immune system, they were discovered in 1960 in con-
nection with organ transplant rejection. To this day they re-
main the primary immunological barrier to this potentially
life-saving procedure.
It was recognized early on that rejection of organ trans-
plants could not be the CTLS raison d'etre, but it was not until
the 1970s that the real task of the killer T cell was discovered:
guarding the body against cancer, and ridding the body of
viruses. Some pathogens, like bacteria, are found swimming
freely in the blood or lymph; these are dealt with by the other
major arm of the immune system: antibodies. Antibodies are
specialized proteins that circulate throughout the body and
bind to pathogens, leading to their rapid elimination. But in
some cases, viruses and other pathogens may actually invade
a living cell inside the body, taking over the cell in order to
reproduce themselves. This can pose a serious threat to the
rest of the body, particularly if the pathogen involved is able
to spread from one cell to another. Left unchecked, such
pathogens can lead to the functional or even actual loss of
large blocks of vital tissue.
Because these pathogens hide inside the cell, they cannot
be "seen" by antibodies patrolling in the lymph fluids outside
41
the cell. Killer T cells are not so easily fooled. They patrol the
entire body, using the same highways and byways of the
bloodstream and lymph used by antibodies. But CTLS are
equipped with special sensors that allow them to detect the
presence of intracellular pathogens. They can spot such
pathogens because all cells in the body display on their sur-
faces samples of the proteins produced inside. If a foreign in-
vader is hiding inside a cell, using the cell's machinery to
make its own proteins, samples of those proteins will eventu-
ally find their way out onto the cell's surface. CTLS know ex-
actly which proteins are normally made by the body and
which aren't. If a CTL encounters a cell displaying a foreign
protein on its surface, it will instantly kill it—no questions
asked; no quarter given. Antibodies cannot do this. (The cells
within a transplanted organ are covered with foreign proteins,
which is why transplants are so vigorously rejected. It doesn't
matter that the transplant could save the recipient's life; from
the CTLS point of view, it is not self— it must be destroyed.)
But how do CTLS do it? How does a killer T cell, once it
decides a given cell in the body is somehow compromised or
foreign, kill that cell? The assumption from the beginning
had been that the CTL must be doing something proactive to
cause the selected target to die. Scientists were looking for a
smoking gun or a bloody knife, for a rope or traces of a poi-
son — anything that might have been used in the lethal hit.
But no matter how hard they looked, or how long they stud-
ied the process from start to end, no truly believable weapon
could be found.
42
And then one day a dozen or so years ago, someone de-

cided to take a closer look at the target cell in its death
throes, just after it had received the "kiss of death" from a
killer T cell. CTLS were mixed with target cells in culture dish-
es outside the body, and followed by microcinematography.
Enlarged images were projected on a screen, run forward and
backward; sped up and slowed down. As expected, the CTLS
approached the targets, bumping and probing and then lock-
ing on tightly for several minutes. But as the target cell was
released from the CTLS embrace, it began to do what every-
one suddenly realized was a classic cellular dance of death.
Its membrane began to ruffle and blister, releasing small par-
ticles that looked very much like apoptotic bodies. And these
bodies did not explode, spewing their contents into the cul-
ture dish; they just sat there, bobbing gently in the nutrient
medium. This sent scientists racing back to the lab to mon-
itor the state of the target cell's DNA during the killing reac-
tion. They were astonished to find that within seconds of the
lethal hit the DNA was gone — fragmented into a million
tiny, useless pieces. And the target cell itself fell gently apart
into apoptotic bodies. There was no doubt about it. Cells se-
lected by CTLS for death are not murdered; they commit
suicide.
So it turned out that all of the years spent looking for
special CTL weapons had, after all was said and done, been
wasted. CTLS are not equipped with weapons for destroying
altered cells. What they are equipped with is knowledge of a
special security code. Every cell in the body—not just a few
43
extraneous cells in the developing fetus — has embedded in

it a self-destruct program. What cm know, uniquely among
all the cells in the body, is how to punch in the security code
that activates that program and ultimately causes the select-
ed cell to commit suicide. The Kevorkian option, you might
say—a kind of assisted suicide. It is absolutely vital to the
overall health of a multicellular organism that any cell com-
promised by radiation or by pathogenic infection be elimi-
nated as quickly as possible, with as little damage to sur-
rounding cells as possible. Of the two types of death we have
seen so far, suicide is far the preferable option from this point
of view.
There is, however, one slight drawback. CTLS are very ef-
fective in seducing compromised cells to commit suicide, but
they are essentially blind in their seduction. A CTL is not
equipped to make judgments about whether the existence of
a strange protein on the surface of a cell truly signals a life-
threatening situation for the organism as a whole. In the ma-
jority of cases non-self proteins on a cell's surface spell trou-
ble, and the resulting cix-induced suicide and loss of cells is
amply justified. Organ transplantion is clearly one exception,
although we can hardly fault the immune system for trying
to do its job in a biologically abnormal situation created by
humans. But there are other exceptions, not at all man-
made, and some of them can lead to disaster. For example,
there are a few microbes that can invade cells and live there
without causing disease; that is to say, they are nonpatho-
genic. If a few cells were lost in the course of eliminating
44
such harmless microorganisms from the body, the damage

done would be of little consequence. But on occasion, for
one reason or another, the CTLS are never quite able to erad-
icate these harmless microbes completely; they may be par-
ticularly well-concealed, or they may spread from cell to cell
more rapidly than CTLS can chase them down. The problem
is, the CTLS never stop trying. Every time they encounter a
cell displaying proteins from the innocuous microbe, the cell
is ordered to commit suicide.
In some cases this can take a terrible toll on the body.
Consider, for example, hepatitis B virus (HBV) infection in
humans. HBV-induced viral hepatitis (also known as serum
hepatitis) is roughly the modern equivalent of the black
plague. It affects more than 300 million people worldwide,
and is one of the world's leading causes of death from infec-
tious disease. HBV induces both an acute and a chronic form
of hepatitis, and is a leading cause of liver cancer. The initial
symptoms of HBV infection are usually unremarkable, bare-
ly more than a mild influenza. When HBV invades cells, it in-
tegrates its own small piece of DNA into the infected cell's
DNA. Once this happens, the cell treats the viral DNA just like
its own. It copies out the HBV instructions for making pro-
teins used in the construction of more HBV, and sends these
instructions out to the cytoplasm for processing. In the
course of this activity some of the viral proteins make their
way out to the cell surface.
The response by CTLS is immediate and vigorous. The
infected cells are quickly induced to commit suicide; in the
45
acute form of the disease the infection is often completely

cleared on this basis in fairly short order. The resultant dam-
age to the liver may be severe, but it is reparable and only
rarely fatal. But in a certain number of cases the disease is not
resolved at the acute stage, and progresses into a more chron-
ic form of HBV hepatitis. This is where the greatest damage
is done. The viral DNA continues to direct production of viral
proteins, which continue to make their way out to the sur-
face of infected liver cells. And the CTLS continue to induce
the infected liver cells to commit suicide. Because the liver
has a certain capacity for self-regeneration, it keeps trying to
replace the missing cells with new ones. But these too be-
come infected as HBV spreads slowly throughout the liver in
an ongoing cycle of death and renewal. Over time the re-
newed, virally reinfected liver tissues become more and more
abnormal, failing to carry out even routine functions such as
metabolising food and manufacturing blood coagulation
products and bile. In some cases, cell loss simply outpaces re-
newal, leading to liver failure and death for the patient. In
other cases the constantly replicating liver cells become can-
cerous and start to grow rapidly and without control. In a
high percentage of advanced cases, particularly in Third
World countries where the necessary intensive care is un-
available or inadequate, the result is death. And yet, as far as
we know, the hepatitis virus itself is absolutely harmless; if
put into culture with human liver cells it will infect them,
but the cells remain perfectly healthy.
There are other examples of CTL-induced mass suicides
46
that result in serious disease or even death for the host or-
ganism. In most cases the pathogen, if left alone, would
probably kill the host anyway; the suicides prompted by CTLS
simply hasten the process. But in other cases, like HBV viral
hepatitis, the pathogen itself is harmless; the damage is done
entirely by the immune system. This sort of immunopathol-
ogy is turning out to be much more common than was orig-
inally thought, and may well underlie a wide range of human
maladies previously considered of uncertain origin.
So the phenomenon of cell suicide, which plays a peace-
ful and positive role in the shaping of embryonic tissues, is
also used to harsh but necessary advantage by killer T cells in
adults. Killer T cells themselves, if they fail to find an in-
fected cell to goad into self-destruction, must also commit
suicide to make room for new T cells with better instincts.
These are all deaths programmed into the overall life plan of
individual animals; they are carried out to give the individ-
ual a chance to stay alive longer and to produce more off-
spring. The suicide of cells turns out to be almost common-
place, a perfectly normal — and essential — part of the
rhythms of animal life.
The origins of cell suicide lie very deep in our evolu-
tionary past. Consider one of the tiniest of multicellular an-
imals: the primitive worm Caenorhabditis elegans. C. elegans
is so small that every single one of its cells can be counted
and accounted for, during its entire lifetime. Like all living
things, it starts as a single cell—an egg—and divides until
it becomes an adult. But C. elegans as an adult comprises
47
only 959 cells. Not 955 cells, not 962 — 959, exactly. Of
these, precisely 302 cells form its tiny nervous system. That
number of cells in a human being would not even show up
as a wrinkle on an eyelid.
For C. elegans, it is only twenty-one days from concep-
tion to death of the organism. But during the transition from
egg to adult, an additional 131 cells are generated that never
make it to the adult stage. Over a period of precisely seven
hours, these 131 cells commit suicide. Why they have to die
is not at all apparent. Were they part of the pattern for some
structure even more ancient than C. elegans, a structure no
longer of use to the adult worm? We do not know what these
cells might have become had they survived. But how they die
is perfectly clear. The sequence of steps followed by these
cells is identical to those taken by cells marked for self-de-
struction in human beings: the destruction of DNA in the cell
nuclei, the detachment from their neighbors, the brief dance
of death, the formation of apoptotic bodies that are engulfed
by neighboring cells. The ritual of cell suicide appears to be
extremely ancient, and almost perfectly preserved across eons
of biological time.
The sameness of apoptosis across such a wide range of
biological situations and evolutionary time, and in the pur-
poses for which it is used and the steps involved in its exe-
cution, led scientists to formulate the notion of programmed
cell death, or PCD. The events that trigger PCD are almost al-
ways the same. Anything that damages a cell's DNA beyond
the point where it can be readily repaired will quickly induce
48
it to commit suicide. Cells also commit suicide in response

to a wide range of extracellular stimuli. CTLS are one obvious
example of such external signals, but apoptosis induced by
CTLS represents a fairly recent co-option of PCD by the im-
mune systems found only in humans and other vertebrates.
The evolutionarily older use of PCD (also shared by verte-
brates, of course) is largely in response to extracellular chem-
ical signals coming into the cell through the plasma mem-
brane. As we saw previously, among the structures embedded
at the cell surface are "mailboxes" into which a wide range of
chemical messages can be deposited. These messages, collec-
tively referred to as cytokines, come from other cells in the
body—sometimes from the brain, sometimes from hor-
mone-producing endocrine glands, and sometimes just from
a neighboring cell. This "chemical chatter" is how cells in
large multicellular animals stay in touch with one another.
But cytokines do not always just represent idle chatter; they
can be the difference between life and death. Many cells re-
quire constant receipt of vital cytokines, such as the growth
factors mentioned earlier, to stay alive. If the growth factors
never arrive, or are withdrawn, the cell will undergo apop-
tosis. Cells that do not require constant supplies of growth
factors to survive may nevertheless be induced to commit
suicide by deposit of a specific instructional cytokine into a
plasma membrane mailbox.
All of this is carefully regulated in the body, ultimately
in keeping with programs embedded in an organism's DNA;
hence the term "programmed cell death." Scientists are now
49
beginning to identify some of the genes that control these

programs. C. elegans has been a particularly powerful tool for
unraveling the genetic basis of PCD. There are genes in C. el-
egans that specifically encode death messages, and cell-sur-
face cytokine receptors (mailboxes) that recognize only those
messages. For cells with death as a preset, time-dependent
default state via PCD, the timely arrival of a critical growth
factor can often override an otherwise certain extinction.
There are also genes in C. elegans that encode messages ca-
pable of reversing the process of PCD once it has been set in
motion. These rescue messages don't arrive in a mailbox; they
are produced within the cell itself, apparently to give the cell
an opportunity to save itself, for example in the face of rela-
tively minor damage to its DNA that may have triggered
apoptosis. If the DNA can be repaired quickly, the cell may be
allowed to live. But in the face of continued indications that
the cell has been compromised—massive DNA damage, the
prolonged absence of a required growth factor, or constant
bombardment with a message to commit suicide—the res-
cue message is drowned out, and the cell starts down the ir-
reversible pathway of apoptosis.
These same messages, and the genes that encode them,
are now being identified in humans, and perhaps not sur-
prisingly they are only modestly different from those found
in C. elegans. The battery of genes and chemicals involved in
the generation, delivery, and processing of death signals in
animal cells is impressively large; programmed cell death is
5O
obviously of great importance to nature. We shall return to

a discussion of this apparently universal form of cell death,
and how it relates to our own mortality, after we ponder an
even larger question: where did obligatory, programmed
death come from?
51
3
Sex, Segregation, and the

Origins of Cellular Death
For man that is born of woman is of few days, and full of

trouble. He flees like a shadow, and continues not.
—The Book of Job
Why death?
From the descriptions in the preceeding two chap-
ters of some of the ways in which cells die, we begin to get a
sense of what death is at the cellular level. Like the death of
the being of which it is a part, the death of a cell is a return
to unconnectedness, to chaos, and to silence. But why do
cells die in the first place? Is there something inherent in the
nature of life that requires all living things to die? To get a
53
sense of the answer to this question, we must go back in time

to the first appearance of cells on earth.
The very first life forms, as we have seen, were not ani-
mals in the ordinary sense of the word, but free-living indi-
vidual cells we now call bacteria. The entire being in this case
consists of just a single cell. Yet by any biological criterion
that would define us as alive, so were they. The earliest of
these organisms represented then, as now, the simplest pos-
sible structure for carrying out the cardinal function of all
living things: the reproduction of their own kind through
replication of their DNA, and transmission of that DNA to
offspring.
But it is less obvious that the earliest forms of these sin-
gle-cell organisms shared then, or share now, the second car-
dinal feature of life as we know it—obligatory, programmed
death. We, like virtually all other multicellular animals, must
die, and there are many mechanisms built into us to be sure
that we do. Some insects measure their life in days; mice live
three years if they're lucky. Humans on rare occasions may
survive to 120 years, some turtles to 200. But all animals
eventually die. Many single-cell organisms may die, as the re-
sult of accident or starvation; in fact the vast majority do.
But there is nothing programmed into them that says they
mwtdie. Death did not appear simultaneously with life. This
is one of the most important and profound statements in all
of biology. At the very least, it deserves repetition: Death is
not inextricably intertwined with the definition of life. Where,
then, did death that cannot be avoided come from? Almost
54
SEX, SEGREGATION. AND THE ORIGINS OF DEATH
certainly, it did not arrive on the scene until a billion or so

years after life first appeared. To understand how pro-
grammed death came about, it will be useful first to take a
brief look at how the earliest single-cell organisms evolved
into more complex life forms.
Of the five kingdoms into which all living things are
commonly divided, single cells comprise one kingdom in its
entirety, and are a significant proportion of two others. The
earliest single-cell organisms, from an evolutionary point of
view, are the bacteria, and these make up the first kingdom,
the kingdom of the Monera (See accompanying Figure).
Monerans have been enormously successful; they are still
around after several billion years of competing with each
other, and with more complex life forms. Today they account
for approximately half of all the biomass on earth. They in-
habit planetary niches extending from frozen arctic tundra
to boiling sulfur vents at the bottom of the sea. The bacteria
inhabiting the world today provide a window to the past that
allows us to guess what the earliest life forms must have
looked like, although clearly the ones we study now must be
considerably different from the first forms that appeared
nearly four billion years ago.
Bacteria came into existence when the earth's atmos-
phere was largely devoid of gaseous oxygen. The gradual in-
crease in the concentration of oxygen in the atmosphere that
occurred around two billion years ago (caused by hydrogen-
hungry, water-splitting photosynthetic cyanobacteria, some
of which would later become parts of plants) was an evolu-
55
CHEMICAL PRECURSORS
OF LIFE
Figure 4. Major evolutionary groups. All classifications of living things

are necessarily artificial, and subject to constant debate and revision. The
scheme shown here is one of the simpler evolutionary "trees" for the major
organismal groups. Protists are the smaller protoctists.
tionary event of major proportions. Oxygen is a deadly, cor-

rosive gas, causing iron to crumble into rust and wreaking
havoc with nearly all of the organic molecules on which life
is based. The monerans began to develop specializations to
56
SEX, SEGREGATION, AND THE O R I G I N S OF DEATH
protect themselves from oxygen. They had to. Those that

didn't simply did not survive.
Although the vast majority of bacteria live their entire
lives as single cells, a number of bacterial species have exper-
imented with multicellularity, which would become the
major evolutionary direction for most succeeding life forms.
Many bacteria live in simple clusters or colonies, trapping
and sharing food. A few, like the Myxobacteria, form rather
elaborate structures calied fruiting bodies that look like mush-
rooms or tiny trees. In general, however, bacteria failed to ex-
plore the tremendous advantages of multicellularity.
Some of the more successful monerans went on to form
new kingdoms of living things: first the kingdom of the
Protoctista (the smaller members of which are called Protista),
and later the kingdom of the Fungi. Most protoctists are
single-cell organisms, like the bacteria. Their kingdom in-
cludes things like the slime molds and amoebae, as well as
cells like Plasmodium, which causes malaria, and advanced
forms of algae, some of which continued the transition from
bacteria to plants.
Several important features came to distinguish the pro-
tists from the earlier monerans. The genetic material of most
bacteria consists of a single, usually circular piece of gene-
bearing DNA. It is attached to the inside of the cell's limiting
membrane, but otherwise floats free and naked in the cyto-
plasm; there is no nucleus. The DNA is naked in the sense
that it is not complexed with the specialized proteins known
as histories. Thus, these earliest cells are called prokaryotes
57
("pre-nucleus cells"). Protoctists and all later cells divide their

generally larger allocation of DNA into multiple chromosomes
complexed with histones and stored in a nucleus. (The name
of these DNA-protein complexes comes from the fact that
they can be stained with certain chemical dyes and actually
seen in microscopes as "colored bodies"—chromosomes.) In
almost all cases these chromosomes are linear, rather than
circular; their tips are capped with special DNA structures
called telomeres, to keep the ends from sticking to themselves
or to other chromosomes. The protoctists and all other nu-
cleated cells are known as eukaryotes ( "true-nucleus cells").
Eu-karyotes also developed something called diploidy: that
is, they began to carry two copies of each chromosome,
rather than a single copy like the monoploid prokaryotes.
(One member of each chromosome pair was inherited from
each of the cell's parents.) Diploidy has the major advantage
that damage to or mutation of a particular gene generally has
less severe consequences than in prokaryotes because there
are two copies of every gene. It also provides an opportuni-
ty for purposeful experimentation by nature with the DNA
composition of genes, leading to possible improvement in
gene function. If an experiment on one copy of a gene fails,
there is always a backup gene to see one through the day.
While remaining single-celled, some of the protoctists
grew to be very large. Size has definite advantages. It cer-
tainly discourages predators, but perhaps of more impor-
tance in the early days of life on earth was the ability to store
food inside the cell for use when nutrients in the environ-
58
SEX, SEGREGATION, AND THE ORIGINS OF DEATH
ment dwindled or disappeared. Protoctists like Pammecium

are easily a million times larger in volume than most bacte-
ria, providing plenty of room for pantries and larders. And
as cells increased in size, they also began to develop a num-
ber of architectural specializations designed to help them
deal with an increasingly complex world. One early special-
ization was the development of a true cytoskeleton, intracel-
lular protein rods that not only helped the larger protist cells
maintain their shape but also came to play a role in locomo-
tion and in feeding. For instance, protoctists and other eu-
karyotes began to use cytoskeletal elements called micro-
tubules in the engulfment of extracellular materials, including
nutrients, in a process called endocytosis.
Although most eukaryotic protoctists are still single-
celled, some of them continued the experiment with multi-
cellularity, and refined it considerably beyond the point
achieved by the most advanced prokaryotes. In multicellular
protoctists we see for the first time communication among
cells living in colonies, and we see the very beginnings of a
specialization of labor among cells. Some multicellular pro-
toctists came to be among the largest living things on earth.
Kelp, for example, is one example of a type of protoctist
called algae; some kelps can grow to be thirty or fourty
meters long.
Protoctists also gradually accumulated internal or-
ganelles to help them survive in an increasingly hostile and
oxygen-filled environment, in some cases through a process
called endosymbiosis. It seems that certain bacteria began to
59
find the interiors of the larger, more advanced protoctists a

reasonable place to live and raise a family. They became par-
asites. Like most successful parasites, these bacteria gave as
good as they took. For example, some bacteria had appar-
ently developed defenses against oxygen; a few even devel-
oped means not just to neutralize oxygen but to use it to
produce energy. This must have impressed certain protoc-
tists, who apparently had taken in some of these oxygen-
breathing bacteria by endocytosis. Instead of digesting them
for food, they converted them into permanent parts of the
protist cell. This may not have been what the bacteria had in
mind, but the experiment turned out to be so successful that
eventually all eukaryotic cells acquired similar intracellular
parasites. We find these bacterial "living fossils" in our own
cells to this day: they are the mitochondria, the energy-pro-
ducing organelles we met in Chapter One. In animals, only
the mitochondria, of all the organelles inside a cell, have their
own DNA, showing their independent biological origin.
Moreover, this DNA is single-stranded and usually circular, is
not associated with histones, and contains genes that are dis-
tinctly prokaryotic rather than eukaryotic in structure.
Although bigger may, in many ways, be better for a cell,
there is a limit to how large a single cell can grow. A cell's vol-
ume grows as the cube of its radius (as does its appetite!)
while the area of its surface membrane — the site where nu-
trients enter and wastes are expelled — increases only as the
square of the radius. At some point in a cell's expansion, its
6O
SEX, S E G R E G A T I O N , AND THE O R I G I N S OF DEATH
surface area will simply become too small to service the huge
internal volume of the cell. Moreover, the need for various
internally produced molecules to operate the cell, which are
encoded by DNA, also increases dramatically with size. A sin-
gle set of internal instructions — even a diploid set—rapid-
ly becomes insufficient. Cells solved this problem in a vari-
ety of ways in their rush to grow larger. Some simply made
more copies of their basic diploid chromosome set, becom-
ing polyploid. A few cells became multinucleate, incorporat-
ing several nuclei, each with only one diploid chromosome
set, into a single large cell. But by far the most successful
strategy was to become multicellular; all life forms beyond
the protoctists, with the exception of a few of the fungi,
became completely and permanently multicellular.
It was somewhere along the pathway from the monerans
to the protoctists, about a billion years ago, that death as we
know it — death as an inescapable consequence of life —
first made its appearance. We will call this form of death pro-
grammed death, to distinguish it from accidental death—
death caused by things like extreme heat or cold, starvation,
physical destruction, or chemical damage. We will also ex-
plore the possible relation of this programmed death of the
organism with the phenomenon of programmed cell death
discussed in the last chapter. (These terms usually mean
something slightly different to the scientists who study them,
but that may be too narrow a view.) But first we will look at
the very beginnings of programmed organismal death as
61
monerans evolved into eukaryotic protists, for it was also

along this pathway, and at about the same time programmed
death appeared, that single-cell organisms first began to ex-
periment with sex in connection with reproduction.
The earliest single-cell monerans reproduced asexually
in a simple process called fission. In this mode of reproduc-
tion, a given cell autonomously replicates its own DNA and
then divides into two perfectly coequal clones of itself, each
clonal offspring receiving one copy of the DNA. These cells
mature and each produces two healthy, coequal clones in
turn. Thus the organism — the single cell— never truly dies.
After all, where is the body? Can there be death in the ab-
sence of a corpse? These cells are in effect immortal. If a sin-
gle asexually reproducing bacterium could be protected from
predators and supplied with adequate food and space to
grow, it would continue clonal expansion through its prog-
eny indefinitely. We would likely never find a single dead cell
in such a culture. Of course, in real life, individual cells can-
not go on clonally expanding forever. Eventually they would
deplete the available resources necessary to sustain life, and
they would—accidentally—die.'
With only a handful of exceptions, single-cell organisms
reproducing exclusively by simple fission lack one feature
1 An average bacterium is about one cubic micrometer in volume and can di-
vide by fission in as little as thirty minutes. Simple arithmetic shows that sixty
to seventy cell divisions later—less than two days after starting to divide —
the progeny of a single bacterium, if they all survived, would be roughly equal
in biomass to all of the human beings presently on earth.
62
that ultimately brings death to all single cells that have sex,
and to all multicellular organisms, including human beings:
senescence, the gradual, programmed aging of cells and the
organisms they make up, independently of events in the en-
vironment. Accidental cell death was around from the very
first appearance of anything we would call life. Death of the
organism through senescence — programmed death—
makes its appearance in evolution at about the same time
that sexual reproduction appears. Both sex and programmed
death began when the vast majority of organisms were still
single cells.
It is important to understand that from a biological
point of view, "sex" and "reproduction" are two entirely
unrelated phenomena. Sex refers only to the exchange or
comingling of all or part of the genetic information —
DNA—between two members of the same species. Repro-
duction is simply that — the reproduction of additional
copies of a given cell. "Sexual reproduction," then, means
the exchange of genetic information in combination with
cellular reproduction.
Sexual reproduction has always been something of a puz-
zle for biologists, especially for evolutionary biologists. From
many points of view, sex is a rather wasteful way to repro-
duce. In fission, one cell gives rise to two; one set of genes is
duplicated in a simple, efficient and relatively low-cost op-
eration, and two new individuals result. In sexual reproduc-
tion, two cells (or two multicellular organisms) must find
each other, determine that they are right for each other, have
63
sex, and then reproduce. Moreover, since most cells engag-

ing in and resulting from sexual reproduction are diploid,
two sets of DNA must be reproduced in each cell instead of
only one. Thus sexual reproduction requires a great deal
more time and energy than simple fission to achieve the
same end result. A cell reproducing by simple fission ought
to be able to outgrow and outmaneuver a cell reproducing
sexually. Yet once sex appeared, it rapidly became the domi-
nant form of reproduction among all subsequent life forms.
Why is this so?
Let's take a closer look at sexual reproduction in life
forms similar to those in which it must have first been tried
during evolution. For single-cell eukaryotes reproducing sex-
ually, sex may involve nothing more than two cells sticking
together and swapping portions of their chromosomal in-
heritance— their DNA—in a process called conjugation1.
After conjugation the cells separate, and then each undergoes
fission into two cells that each receive identical copies of
slightly scrambled and recombined chromosomes. The act
of conjugation — the sex part of the process — starts with
two cells and ends with two cells; no additional cells have
been created. For single-cell eukaryotes, only when conjuga-
tion is followed by independent fission of the participating
1
It should be noted that a process termed conjugation has been described for
prokaryotic organisms as well. Although bearing some similarities to conju-
gation in eukaryotes, the process in prokaryotes is fundamentally different,
and not obviously related evolutionarily to conjugation in eukaryotes as de-
scribed here.
64
cells can we say that sexual reproduction has taken place. The
most important consequence of this act is that the new cells
produced as a result of conjugation, and the offspring they
subsequently produce by fission, are genetically different from
the parent cells prior to conjugation. This is quite unlike the
process of fission in asexual reproduction, where the parent
and daughter cells are usually genetically identical. This dif-
ference almost certainly underlies the great advantage of sex,
but in the evolutionary line leading to human beings it also
contains the seed of a serious problem—a problem that na-
ture ultimately solved by inventing obligatory senescence
and death.
This basic process of mixing and exchanging genetic in-
formation—sex—is used in connection with reproduction
today by some prokaryotes, by the majority of single-cell
protoctists and fungi, and in one form or another by most
multicellular organisms. There are many theories concern-
ing the origin and evolutionary driving forces behind sex.
Whatever else may be said about it, sex unquestionably en-
hances genetic variation, which is one way species are able to
adapt to a changing environment. Different combinations
of genetic information generated during mating allow indi-
vidual offspring to adapt rapidly, albeit with differing effi-
ciencies, to environmental change; those individuals who
successfully adapt are selected for survival and further repro-
duction.
A second major advantage of sex is that it allows for the
repair or elimination of genetic mistakes — the mutations
65
that creep into individual genes, causing them to lose their

function, whether that function is coding for a particular
protein, or regulating some cellular response. Genes are writ-
ten into the DNA of chromosomes. Over time, different in-
dividuals will have accumulated different combinations of
defective genes. During sexual reproduction, the chromo-
somes (and thus the genes) are randomly mixed and redis-
tributed to offspring. Since sex in eukaryotes takes place
mostly between diploid individuals, it is unlikely that two
individuals having sex will have accumulated exactly the
same mutations; mutations in a given gene of one sex
partner will most often be compensated in the offspring by
the unaltered copy of this gene from the other partner.
Moreover, if by chance an offspring should inherit two
copies of a mutated gene, that individual may not survive to
reproductive age, thus reducing the number of "bad" copies
of that gene floating around in the population. Such .indi-
viduals die (by what we would describe as accidental cell
death), and their defective genes die with them.
While sex in the sense of transfer of DNA between cells
actually made an appearance among some of the prokary-
otes, and while sexual reproduction took several forms
among different eukaryotic species, the process that devel-
oped in single-cell eukaryotes like the Paramecium is most
likely ancestral to the way we ourselves use sex. It also
demonstrates quite clearly how the coming of sex eventual-
ly led to compulsory, programmed death in that line of evo-
lution leading to multicellular organisms like us.
66
Paramecia are one of a large number of species of ciliat-

ed organisms found in freshwater ponds throughout the
world. Although single-celled, these protoctists are enormous
— easily a million times larger in volume than most bacte-
ria. They use hairlike cilia beating in controlled synchrony
to move about, a great advantage for a single cell in terms of
escaping danger or finding food. They have even developed
a specialized membrane region at one end of the cell that
serves as a mouth, and a similar region at the other end that
serves as an anus for discharging wastes. Like all eukaryotes,
paramecia keep their DNA in a nucleus, of which, impor-
tantly, they have more than one kind.
Beginning in the late nineteenth century, biologists in-
terested in cell growth and cell death began to suspect that
there might be a fundamental difference between single bac-
terial cells and the larger single-cell protists like paramecia.
Whereas bacterial growth did seem to be limited only by
food and space, several investigators thought they observed
undeniable signs of senescence—obligatory, time-dependent
degeneration and death—in some of the protoctists. For ex-
ample, if a single paramecium is placed in a glass culture dish
(in vitro) with unlimited food and space to grow, it will begin
clonal expansion by simple fission just as asexually repro-
ducing bacteria do. But before too long the rate of clonal ex-
pansion among the progeny of this single paramecium will
begin to slow. If the cells continue to reproduce exclusively
by fission, this slowing process will continue, and after a total
of about 200 cell divisions, the clonal progeny will stop di-
67
viding and die. However, if somewhere along the way some

of the progeny conj ugate—have sex—their senescence clock
is reset. The clonal progeny of those cells that have sex resume
a rapid rate of growth and expansion by vigorous asexual fis-
sion. The progeny of their siblings and cousins that fail to
conjugate continue to senesce and eventually die.
In ciliates reproducing sexually, the rejuvenated progeny
produced by recent conjugation seem to go through a mat-
uration period similar to prepubescence in animals in that
they cannot themselves have sex. But they also start life with
a predetermined life span. Their senescence clock begins to
tick, and they must themselves at some point abandon sim-
ple fission and reproduce sexually if they are to reset their
own clock and survive through their progeny. Immortality
for bacteria reproducing only by fission is granted automat-
ically; immortality for everyone else depends on having sex.1
Why should the introduction of sex into reproduction
have been accompanied by the advent of senescence and pro-
grammed death? One reason is related to a problem pointed
out earlier: the progeny of cells reproducing sexually are ge-
netically different from the parent cells. A second reason may
be related to a feature we see for the first time in paramecia
It is worth noting here that the rejuvenation process in paramecia and other
ciliates is tied more to the reproductive act itself than to the exchange of DNA
per se, which is the strict definition of sex. Some ciliates are capable of self-
fertilization, in which the DNA of a single cell is reshuffled and rearranged (au-
togamy). Although no new DNA is introduced, the cell is nonetheless rejuve-
nated in the same way as a cell having true sex.
68
and other protists reproducing by sexual means: the segrega-

tion of DNA to be used for reproductive purposes (conjugation)
from the DNA used to direct the day-to-day operation of the cell.
Each type of DNA is kept in a separate nucleus. The macronu-
cleus houses the DNA used to direct the production of mes-
sages to be sent out to the cell's ribosomes for conversion into
proteins needed by the cell to conduct its daily business of
eating, respiring, moving about, and so on. The chromo-
somes, and even selected fragments of chromosomes, are
often replicated hundreds of times over in the macronucle-
us to generate enough DNA to run these very large cells.
Paramecia also have a smaller, relatively inactive mi-
cronucleus, which contains a single diploid set of chromo-
somes. Each chromosome in the micronucleus wears its his-
tone coat rather tightly, and for most of the life cycle of the
cell lies unread and unused. Only when the cell is about to
divide does the micronucleus become active. When parame-
cia reproduce asexually, both the macronucleus and the mi-
cronucleus divide their DNA in two, providing each offspring
with a new copy of each type of nucleus. The macronucleus
simply divides whatever DNA it has on hand into two pots,
one for each offspring. During its brief awakening at the
time of cell division, the micronucleus makes a complete and
faithful replica of its DNA; one offspring receives the original
copy, and one the replica. The newly minted micronucleus
goes immediately into hybernation, as in the parent cell, and
the macronucleus resumes the day-to-day operation of the
new offspring.
69
Figure 5. Sexual reproduction in ciliates. A. Two genetically different
ciliates, each with a macronucleus (M) and a micronucleus (m). B. The two
ciliates fuse in the first step of conjugation, and the macronuclei and
micronuclei move to opposite ends of the cell. C. Each micronucleus
divides once by meiosis, and D. the daughter micronuclei each divide
again, to produce four haploid micronuclei. E. Three of the four haploid
micronuclei disappear. F. The remaining micronucleus divides once more,
to produce two identical micronuclei, and then the two conjugants
exchange one micronucleus (G). H. The two haploid micronuclei fuse to
produce a single diploid micronucleus. I. The new micronuclei each direct
the production of a new macronucleus; the old macronucleus begins to
disintegrate. J. The two ciliates disengage, and the nuclei assume their
starting positions in the cell. The exconjugates are now genetically identical
to one another, but genetically different from either of the two starting
cells. Each will go on to produce genetically identical daughters by simple
fission.
SEX, SEGREGATION. AND THE O R I G I N S OF DEATH
But if the cell finds another cell interested in conjuga-

tion (see accompanying Figure), then the micronuclei play
an additional role. The two conjugation partners prepare to
combine and exchange portions of their micronuclear DNA.
This involves an important step that is a feature of sexual re-
production in all eukaryotic cells. The micronuclei are
diploid; in sexual reproduction, two conjugating paramecia
are going to exchange micronuclei and fuse them, mixing
their chromosomes together. This would result in a mi-
cronucleus with four sets of chromosomes rather than two.
These conjugated micronuclei would be tetraploid, and sub-
sequent mating would produce micronuclei with eight chro-
mosomes, then sixteen, and so on ad infinitum. So before
the micronuclei are exchanged between two conjugating cells
they must undergo meiosis. In meiosis, each micronucleus
divides into two micronuclei with only a single chromosome
set; they become haploid. Like their monoploid moneran an-
cestors that reproduced by simple fission, they now have
only a single copy of each chromosome. Each of these new
micronuclei assembles its haploid chromosome set by ran-
domly choosing among the maternal and paternal member
of each chromosome pair in the parent micronucleus from
which it arises. Thus the micronucleus at this stage is already
different from the micronucleus from which it is derived.
Once meiosis is complete, the two haploid micronuclei
in paramecia divide again, producing four haploid micronu-
clei. One of these is randomly selected for use in the conju-
gation process; the others are destroyed. The selected mi-
71
cronuclei divide one last time, and then the two conjugating
cells exchange one of their haploid micronuclei. Each cell
immediately fuses its mixed pair into a single, diploid mi-
cronucleus. These diploid micronuclei define the new indi-
viduals resulting from the conjugation process. It is at this
stage that compensation for a bad gene in one of the con-
tributing haploid sets can take place. This is also the stage at
which a few unfortunate individuals may inherit two defec-
tive copies of a gene, and die as a result.
This same process takes place in human reproduction;
sperm and ova in their mature state, ready for reproduction,
are made haploid through meiosis. After fertilization, die nu-
clei of the two cells fuse, creating a diploid cell which is the
foundation cell of a new human being. But an additional
process takes place in ciliates during sexual reproduction. Just
as the conjugants are about to separate, the newly created mi-
cronuclei undergo additional replications; this time some of
the daughter micronuclei continue replicating portions of
their DNA to make a new macronucleus. And then the old
macronucleus, sitting alone at one end of the cell, begins to
degenerate; it dies.
What do ciliated protoctists have to do with human be-
ings? What can they tell us about our own death? A great
deal. For it is only in connection with sexual reproduction
seen in protoctists like paramecia that we encounter for the
first time the generation of DNA that is not transmitted to the
next generation. This segregation of DNA into two compart-
ments (the macronucleus and the micronucleus) never hap-
72
pens in bacteria or even higher organisms reproducing asex-

ually. And what becomes of this excess DNA not used for re-
production? It is destroyed. In fact, one could very well make
the case that it is in the programmed death of the macronuclei
of early eukaryotes like paramecia that our own corporeal deaths
are foreshadowed. The micronuclear DNA is sequestered and
protected during the life cycle of these cells. It is used solely
for recombination with the DNA from another individual in
sexual reproduction. Copies of this recombined, biparental
DNA will be passed to the next generation of cells. The rest of
the DNA, partitioned off in the macronucleus, is now super-
fluous. It cannot be passed on to the next generation, be-
cause the next generation will be defined genetically by the
newly recombined micronuclear DNA. What would the next
generation do with this used, genetically different DNA?
Moreover, this DNA will have accumulated potentially harm-
ful mutations in the course of previous rounds of asexual re-
production. These mutations are not compensated for or
corrected by meiotic sex. The new micronucleus must create
a new macronucleus, with new DNA, to run the new cells.
Otherwise, what was the point of recombining the mi-
cronuclear DNA? If we follow the fate of the old macronuclei
forward from these early eukaryotes, we will see all too clear-
ly why we ourselves must one day die.
Admittedly, not all protoctists incorporating sex into
their reproductive activities went through the stage repre-
sented by the ciliates; not all of them began the process of se-
questration of reproductive DNA within the context of a sin-
73
gle cell. But very shortly after ciliates segregated DNA within
themselves, this segregation and protection of DNA destined
for reproductive use would be formalized for all time when
some of the protoctists (and most subsequent life forms)
became permanently multicellular. As we have seen, multi-
cellularity was explored by bacteria, possibly even before eu-
karyotes ever appeared. But multicellularity was taken to a
completely new level by protoctists and subsequent life
forms. And the evolutionary line passing through this new
type of multicellularity leads directly to human beings.
Multicellularity has many advantages, among which is
certainly size. Multicellularity solves many of the problems
mentioned earlier that arise in connection with larger indi-
vidual cells — too much volume for too little surface, and
not enough DNA to direct the operation of very large cells. In
multicellular animals, large size as an organism can be
achieved with rather ordinary-sized cells. But the greatest ad-
vantage of all, as noted earlier, is the ability to assign specif-
ic biological functions to different cell types.
Once eukaryotes became multicellular, not only would
reproductive DNA be kept in separate nuclei; it would be se-
questered in just a few special cells in the body, which in hu-
mans and other animals are called germ cells. Like micronu-
clei, germ cells have only one function: the transmission of
DNA from one generation to the next via sexual reproduction.
The rest of the cells in the body—the somatic cells—receive
identical sets of chromosomal DNA, but they use this DNA
only to carry out the body's workaday, nonreproductive
74
functions. The somatic cells in our bodies divide only by

simple fission. They do not exchange or recombine DNA with
one another—they do not undergo meiosis or have sex. The
only purpose of somatic cells, from nature's point of view, is to
optimize the survival and function of the true guardians of the
DNA, the germ cells. The DNA passed forward to the next gen-
eration in germ cells will have been changed, through mix-
ing and recombination with the DNA of another. Many of its
mistakes will have been corrected or otherwise compensated
for. But like the macronuclear DNA of paramecia, unrecom-
bined somatic cell DNA becomes not just redundant, but ir-
relevant. It could also become dangerous. Since it is not sub-
jected to random recombination and segregation like germ
cell DNA, it would continue to harbor the accumulated mu-
tations of untold numbers of generations, until it became ge-
netic garbage unable to properly run a cell.
Prior to protoctists like paramecia and their relatives, the
somatic DNA was the germline DNA. Prior to multicellular an-
imals, the somatic cell was the germ cell. The haploid germ
cells seen in animals like us are in a very real sense the heirs
of the micronuclei, and the lineal descendants of the early
monerans and the asexual protoctists; only the germ cells re-
tain the potential for immortality. At some point in the life
cycle of the individual, they may leave the body proper, com-
bine with other germ cells, and continue dividing to produce
progeny that divide and generate yet another multicellular
organism with another set of germ cells. When this happens,
the germ-cell senescence clock is reset, just as it was after
75
conjugation in paramecia. The rest of the cells of the body,

the somatic cells, are condemned — programmed—to
senesce and die. Once they have carried out their task of en-
suring the survival of the germ cells, they and their excess
DNA are no longer needed.
Our own bodies are no different. All of our somatic cells
will get old, and they will die. Sex can save our germ cells,
but it cannot save us. With paramecia and other single-cell
eukaryotes, the organism can be rejuvenated by sex because
the organism and the germ cell are synonymous. Once the
organismal (somatic) DNA was partitioned off from the re-
productive (germline) DNA, sex may have become mandato-
ry— even enjoyable — but not rejuvenating. Not for so-
matic cells. Not for us.
The drive toward ever-increasing size, and eventually
multicellularity, led to the creation of extra-germinal (so-
matic) DNA. The advent of sex in reproduction made it nec-
essary to destroy the somatic DNA at the end of each genera-
tion. We do not know which of these two events came first,
but we do know that the creation and segregation of nonre-
productive DNA never occurred in cells reproducing asexual-
ly. Death may not be necessary for life, but programmed
death is apparently necessary to realize the full biological ad-
vantage of sex as a part of reproduction. Not all cells that ex-
perimented with sex during evolution created somatic DNA,
but the protoctists on the evolutionary path leading to hu-
mans and other animals did. In part this was a response to
the need for more DNA to direct the operation of ever larger
76
individuals. But once this tendency was combined with sex,

death was the inevitable outcome.
Just as with asexual single-cell organisms, of course,
many of our somatic cells will die before their time for rea-
sons other than senescence, like the heart cell in Chapter
One that succumbed to ischemia. Others will die from in-
fection or poisoning, or will be killed by our own immune
systems in the process of clearing an infection. If we lose a
limb in an accident, the cells of that lost limb will die with-
in minutes of its disconnection from the body. But all the
somatic cells in our bodies that somehow manage to escape
accidental death or death caused by disease will still one day
die of "natural causes" — of senescence. We will explore the
way in which this happens in the next chapter.
77
4
From Sex to Death:

The Puzzle of Senescence
O how shall summer's honey breath holdout

Against the wreckful siege of battering days?
—William Shakespeare
Senescence is the clock that marks our passage

through life; if we escape all other forms of death, when this
clock runs down we die. But if the death of an organism can
ultimately be accounted for by the deaths of individual cells,
then what does senescence mean at the cellular level? How
does a cell grow old? When a cell dies as a result of senes-
cence, how does it die? We have said that among all the cells
in the body, only germ cells retain the potential for immor-
79
tality; only germ cells are able to reset the senescence clock.
How do they do this? These are among the most important
questions in the study of aging, and are of great interest to
cell and molecular biologists as well.
There are many theories about the biological mecha-
nisms underlying senescence, but they all fit into one of two
categories. One school of thought (the "catastrophists") be-
lieves that as cells stop dividing, at about the time an organ-
ism reaches physical maturity, synthesis of the various mol-
ecules of which they are made slows greatly, or even stops. In
cells that divide repeatedly, like single-cell organisms repro-
ducing by fission, or like the cells making up a growing em-
bryo or a young child, these molecules are constantly re-
newed and the component parts of each cell remain young
and healthy. But in a mature organism, one that has reached
the limits of its growth, this pattern of ongoing cellular re-
placement and renewal comes to an end. Over time, the
molecules simply wear out and are no longer able to do their
job. Eventually, if enough copies of critical molecules lose
their function, the result for the cell is catastrophic; its struc-
ture begins to erode, or it is not be able to carry out vital
tasks, such as energy production or movement; perhaps some
of the critical membrane pumps break down.
The second school of thought (the "genetic program-
mers") believes the answer lies deeper. Given that the early
stages of growth and development, which are also time-de-
pendent and irreversible, are under strict genetic direction,
why would we assume that the continuation of these stages
8O
FROM SEX TO DEATH
into decay and death is not? Moreover, if it were simply a

matter of parts wearing out, what would explain the tremen-
dous differences in life span of multicellular organisms that
are all made of exactly the same basic molecular materials?
There is no real difference, after all, between the proteins in
a mouse and the proteins in a human. Why does one animal
live three years, and the other eighty? Perhaps in the world
of multicellular organisms death is too important to be left
to chance. Perhaps death is genetically programmed, in the
same way eye color or cholesterol level is.
As is so often the case in biology, when two schools of
thought each have sound and convincing arguments to put
forward, both are probably right. The two viewpoints just
presented are not mutually exclusive. The molecule we
would have to worry most about in terms of wear is very
likely DNA—the repository of all genetic control. DNA is
constantly threatened with mutation, either internally, from
mistakes made during the replication of DNA that accompa-
nies cell division, or from external agents such as chemicals
or radiation. Haploid DNA in germ cells undergoing meiosis
is readily accessible and easy to repair, and germ cells are
literally loaded with the equipment to do it: DNA-repair en-
zymes. Somatic cells have a much shorter supply of these en-
zymes, especially as they get older, and so their DNA is much
more difficult to repair. As a result, somatic cells gradually
begin to accumulate uncorrected mutations. To the extent
that this mutant DNA is called upon to make more proteins
needed by the cell, it might well make faulty proteins that
81
would compound the problem of existing normal proteins

wearing out. The rate at which the accumulation of lethal
mutations happens in different organisms could be dictated
by the efficiency of the DNA repair enzymes or by their rate
of disappearance from somatic cells, either of which could be
genetically programmed.
There is reasonably good evidence that senescence in cil-
iated protozoa that fail to have sex is in fact largely caused by
the accumulation of mutations in macronuclear DNA. If
macronuclear (somatic) DNA were passed on from generation
to generation, without the corrective repairs available to
germ-cell DNA, this DNA would eventually mutate into some-
thing completely useless. On the other hand, micronuclei
(like germ cells) have high levels of DNA repair enzymes,
which are themselves encoded by genes in the DNA. Thus in
those protists that have sex, it is clear that limited life span is
a genetically determined property of the organism, and pro-
ceeds at a specified pace independently of conditions outside
the cell.
There is also evidence in favor of the genetic determina-
tion of longevity in humans. For example, studies with twins
show that genetically identical twins on average die thirty-six
months apart; their lifespans are very similar. By comparison,
fraternal twins die seventy-five months apart, and randomly
selected siblings have an average time between deaths of 106
months. The closer two individuals are genetically, the closer
their life spans. There are also genetically based diseases in
which the aging process is greatly accelerated.
82
FROM SEX TO DEATH
One such disease is the rare but tragic Hutchison-

Gilford progeria syndrome, in which children undergo the en-
tire human aging process, through death, in about fifteen
years. The first changes appear in the affected children's skin,
which in the first year or two of life becomes wrinkled, thin,
and parchment-like, almost translucent. Their faces begin to
look old, with delicate blue veins criss-crossing their fore-
heads. A few years later, their hair begins to fall out; what is
left soon turns gray. These children never thrive; they are
chronically underweight and shorter than normal. They lose
their body fat, just as old people do. They have skeletal prob-
lems, and they become wizened and bent before their time.
They rarely enter puberty, seeming to progress directly into
old age. Frail and shriveled, they usually die of cardiovascu-
lar disease or stroke before the end of their second decade of
life. Everyone agrees that this phenomenon of premature
aging is genetic in origin, although the precise nature of the
gene defect and its mode of transmission are unknown.
Obviously this gene, whatever it is, is critically involved in
the aging process.
A dramatic demonstration of senescence at the cellular
level, one that also points to genetic control of aging, can be
seen in isolated human cells taken from healthy individuals
and cultured outside the body. Human connective tissue can
be dissociated into single cells by mild digestion widi certain
enzymes. The resulting single cells are mostly of a type called
fibroblasts—the "worker cells" in Chapter One that helped
make scar tissue in our patient's damaged heart. Fibroblasts
83
Figure 6. Progeric child. This is an artist's composite of a male child, age
approximately thirteen, showing the classic signs of the Hutchison-Gilford
syndrome, or progeria. The head is larger than normal, with rather small
facial features including a slightly beaked nose and a receding chin. There is
extensive hair loss, and fine, bluish veins on the scalp and forehead. The
skin over most of the body is sagging and wrinkled. Arthritis is evident in
many of the joints, particularly the knees and elbows.
FROM SEX TO DEATH
are not unlike many single-cell organisms; although they are

many times larger, each cell is nonetheless a discrete, self-
contained entity with but a single diploid set of the DNA
blueprints representing the person it was taken from. If put
into culture with an unlimited supply of nutrients, and kept
at body temperature in a humid environment with an ap-
propriate balance of oxygen, nitrogen, and co2, f ibroblasts
immediately start dividing, reproducing themselves asexual-
ly exactly as bacteria or nonconjugating paramecia would.
Each division produces two identical daughter cells. Though
such a large and complicated cell takes much longer to di-
vide than a bacterium, or even a paramecium, fibroblasts
nonetheless enter into a state of smooth and essentially un-
interrupted proliferation.
The difference between our cells and single-cell prokary-
otes like bacteria becomes apparent only after a few weeks in
culture. As long as we keep replenishing the nutrients in bac-
terial cultures and siphon off the excess bacteria to avoid
crowding, the bacterial cell division rate never changes. But
human fibroblasts, no matter what we do to them, no mat-
ter how often we change the medium or enrich it, eventual-
ly begin to slow down. It takes longer and longer for each cell
to divide into two daughter cells. Finally, like asexual para-
mecia, fibroblasts simply stop dividing, and nothing we can
do will make them start up again. It is as if they had been fol-
lowing some internal program for proliferation, and had
come to the end of that program. A week or so after the final
round of cell division, they curl up and die.
85
This phenomenon was investigated in great detail by the

renowned cell biologist Leonard Hayflick in the 1970s and
1980s. He found that fibroblasts isolated from a human
fetus could undergo, on average, a total of fifty rounds of cell
division outside the body before finally stopping. Fibroblasts
isolated from a middle-aged person might divide twenty or
thirty times before slowing down, degenerating and dying.
Cells taken from a very old person divided only a dozen or
so times, and only very slowly. Remarkably, if fetal fibrob-
lasts were stopped after twenty doublings, frozen and stored
in liquid nitrogen (for up to twelve years), and then returned
to culture, they would divide just about thirty more times
before slowing and dying. These cells appeared to continue
on toward completion of the program begun years earlier, as
if nothing had happened, as if time itself had stopped.
These experiments with human cells in culture have
been repeated using fibroblasts isolated from children af-
flicted with progeria. Tiny pieces of skin were removed from
three such children, from their parents, and from normal
children of the same age and sex as the progeric children.
The fibroblasts from the skin of the healthy children took
off rapidly in culture, dividing frequently and expanding at
a great rate. The cells taken from the parents grew well for
awhile and then slowed down, lagging far behind the cells
from the healthy children. The fibroblasts from the proger-
ic children grew even more slowly than those from the par-
ents. They divided a few times, stopped, and then died, fore-
86
FROM SEX TO DEATH
shadowing the early death awaiting the children from whom

they came.
All these studies have contributed to the notion that an-
imal cells have a built-in program limiting their lives to a pre-
determined span. In the case of human fibroblasts this pro-
gram can be observed directly in the number of doublings
they undergo before they die. In other cells that do not nor-
mally divide when placed in culture — muscle cells, for ex-
ample, or nerve cells — the gradual loss of other functions
may be more important, but the principle is the same.
How do cells that reach the limit of their ability to di-
vide and function die? Again we can get a glimpse of what
may be involved by looking at experiments carried out in
one of the protists, in this case a single-cell ciliated cousin of
the paramecia called Tetrahymena. Like paramecia, tetrahy-
mena have two nuclei — a macronucleus, containing DNA
used to run the cell, and a micronucleus, housing DNA used
solely for reproductive purposes. And like paramecia,
tetrahymena senesce in the absence of sex. When tetrahy-
mena conjugate and are preparing to produce daughter cells,
the micronuclei divide to produce new micronuclei, which
then go on to make new macronuclei. The old macronuclei
degenerate in a familiar way: the chromosomes begin to
condense, and the DNA begins to fragment into tiny, un-
readable pieces; the membrane of the old macronucleus
breaks down, and soon the entire nucleus disappears. The
degraded materials are used by the cell as food. This process
87
is very specific for the old macronucleus; the new macronu-

clei (and the micronuclei) are untouched. Somehow the old
macronucleus has been told to initiate a program of self-de-
struction, and as far as can be discerned, this program pro-
duces exactly the same nuclear destruction that accompanies
apoptosis in higher organisms. Recent studies suggest that at
least part of the death program is encoded by genes in the
old macronucleus itself. As we saw for other cells, one of the
last acts of the old macronucleus is to transcribe genes gov-
erning its own death.
The lesson of the protoctists is thus that the repair of so-
matic (nonreproductive) DNA is troublesome, expensive, and
in the end just not worth it. Besides, as we saw earlier, so-
matic DNA must be changed to reflect the composition of die
new, sexually produced reproductive DNA. This would be
difficult enough in the macronuclear DNA of single-cell cili-
ates; in multicellular animals, it is out of the question. It is
easier simply to destroy the old somatic DNA and start over.
If that somatic DNA is in separate cells, the cells die too.
Unfortunately, those cells are us.
So in fact, programmed cell death is even older than the
nematode C. elegans described in an earlier chapter; it goes
all the way back to the earliest sexually reproducing single
cells. The example of the protoctists raises a startling possi-
bility for multicellular animals: is death at the end of senes-
cence ultimately the result of cell suicide? Cell suicide —
apoptosis — as we ordinarily think of it in multicellular or-
ganisms might seem at first glance to have little to do with
88
FROM SEX TO DEATH
senescence. Animal cells commit suicide most commonly

during the active years of an animal's life, particularly during
embryonic stages in the shaping of an emerging life form.
Cell suicide may come into play in the middle years as a de-
fense against radiation damage, or during the course of an
immune response. Senescence is seen only at the very end of
an animal's life, as a process leading up to the destruction of
unneeded somatic cells. But are apoptosis and death as the
endpoint of senescence really different? Both are strongly be-
lieved to be genetically programmed and regulated. Both
types of death seem to have arisen at exactly the same time
in evolution. In tetrahymena and paramecia, at least, the
function of macronuclear "suicide" is related to sexual re-
production: the need to dispose of DMA not transmitted to
the next generation. But isn't that exactly what the elimina-
tion of unneeded somatic cells is all about?
One way to gain some insight into the relationship be-
tween senescence and programmed cell death is to observe
what happens to somatic cells when they come to the end of
the "Hayflick limit." When we monitor fibroblasts during
the final stages of their lives in culture, we find that over time
they lose their ability to divide, and eventually simply sit
there, waiting for death. When death finally comes, it ex-
hibits all the classic signs of apoptosis — membrane blister-
ing, nuclear disintegration, the formation of apoptotic bod-
ies and so forth. The fibroblasts in fact die by what we would
have called suicide in younger cells. Is the death of cells at the
end of the life of a multicellular animal also suicide? Does
89
programmed cell death determine the lifespan of a cell, and

thus of an individual?
It is perhaps unlikely that all of the features we associate
with senescence — for example, the tissue degeneration seen
in old people or in progeric children — are part of the same
program as apoptosis per se. But it is entirely likely that at
some point, as cells gradually lose their ability to function as
a result of the action of genes controlling aging, they realize
that the game is up and that it is time to step aside. It is time
to do what all somatic cells must do once they have finished
their task. That task is simply to assure the survival of the
guardians of the DNA, the germ cells. When that task is done,
they—and we—must die. Suicide may be as graceful a way
as any.
We pointed out earlier that germ cells are like asexually
reproducing single cells, and like the micronuclei of some of
the protoctists, in that they are potentially immortal. Part
of the reason for this may be that they are able to purge
harmful mutations from their DNA. We ourselves descend
from these immortal cells; how do we become mortal? What
happens to a potentially immortal haploid germ cell after fer-
tilization, when it fuses with another potentially immortal
haploid germ cell to become a diploid zygote; what is the
"mortality state" of this founding cell as it embarks on the
construction of a completely new individual who will be
mortal? When this single cell divides into two, and then four
and then eight, is the property of immortality lost, or shared
equally among all the progeny, or is it perhaps hoarded and
9O
FROM SEX TO DEATH
nurtured by just one or a few of these cells that remain im-

mortal, eventually giving rise in a direct lineal fashion to the
new individual's germ cells?
The answer seems to be that at least for awhile, all the
cells of a growing human embryo retain the property of im-
mortality. And then, as the embryo begins to undergo the se-
ries of cellular specializations known as differentiation, which
eventually give rise to individual organs and tissues, all of the
cells of the embryo become mortal; they begin the process of
senescence, albeit without any immediately visible impact on
the developing individual. But the pathway leading to death
is set in motion before the embryo even assumes human
form, and the immortality of the germ cells is conditional: it
will have to be restored somehow at a later stage.
The immortality of the cells of the early embryo can be
seen in the laboratory through the study of embryonal stem
cells (ES cells). These cells, normally prepared from mice, have
been used by many laboratories around the world to produce
genetically altered strains of mice — most commonly, mice
that are missing a specific gene. The close study of such mice
can reveal a great deal about the role of the gene in question.
ES cells are obtained by removing the developing mouse
embryo from the oviduct after fertilization but before im-
plantation in the uterine wall. At this stage the embryo has
perhaps sixty to 100 cells. Scientists have been able to disso-
ciate this ball of cells, called a blastocyst, into single cells and
grow them in vitro. By carefully manipulating die culture en-
vironment, it is possible to prevent the ES cells from pro-
91
ceeding down the pathway to differentiation, and yet allow

them to continue dividing. ES cells have been maintained
this way through many dozens of passages in vitro, enabling
just a few harvested cells to expand into many millions.
If these cells are reintroduced into a freshly isolated blas-
tocyst, they will participate in the creation of a perfectly nor-
mal new individual. They will contribute to any and all parts
of that new individual, including the germ cells, showing
that they have not lost any of their capacity for generation;
in the language of developmental biologists, they have re-
mained totipotent. By selective mating of the offspring of
mice produced in this fashion, it is possible to produce a
mouse that is genetically identical to the donor of the ES
cells, a mouse which will in turn produce offspring, includ-
ing germ cells, of the donor type. Thus we can conclude that
the cells from the early embryo — the ES cells—were both
totipotent and immortal. But if we harvest cells from later
stages of embryonic development, this type of experiment
will not work; it is clear that cells beyond the ES stage (the
blastocyst stage) have all lost their capacity for producing a
new individual, and that they are all mortal. They have
begun the process of senescence, and although they may
grow for a longer time in vitro than cells from an adult, they
will in fact all die.
The notion that mortality is a specific, genetically con-
trolled program is an important one. From an evolutionary
point of view, the appearance of senescence and death in so-
matic cells and the resulting destruction of somatic DNA was
92
FROM SEX TO DEATH
a "gain of function" event; these properties did not exist in

cells for the first billion or so years that life existed. Once
senescence and programmed death appeared in certain or-
ganisms, they—and the genes underwriting them — be-
came "fixed" because they were advantageous. Senescence
and death have to be actively worked toward; they do not
just happen. Somatic cells even have a number of safeguards
built in to make sure they do not backslide and try to be-
come immortal. But to whom or to what are these programs
advantageous? Who or what profits from our aging and
death? The only answer possible, the only conceivable ben-
eficiary, is the DNA being passed from the previous genera-
tion to the next generation via the germ cells. And this DNA
will carry with it instructions for the senescence and death
of the next generation of somatic cells.
Can human somatic cells ever escape the fate pro-
grammed in their genes? Can they ever escape the Hayflick
limit and become immortal? Consider the extraordinary case
of Henrietta Lacks, a thirty-year-old African-American and
an apparently healthy mother of four who was diagnosed
with cervical cancer in February 1951. Gynecological and
breast cancers in young women are relatively rare, and usu-
ally difficult to treat successfully. Henrietta Lacks was
admitted to the prestigious Johns Hopkins Hospital in
Baltimore, where she lived. A small piece of her tumor was
removed for study by a pathologist, who confirmed that it
was a particularly aggressive form of cancer. She was imme-
diately given radiation treatment in the area of the tumor,
93
and the initial results were encouraging. On several follow-

up visits over the next few months, no tumor could be seen
by direct visual examination. However, during the summer
of 1951 she complained of increasing abdominal and kidney
pain. Although cleared from her cervix by the radiation treat-
ments, the tumor had spread to other nearby organs. Despite
heroic efforts to save her, Henrietta Lacks died in October of
that year, barely eight months after the initial diagnosis. It
was indeed an unusually aggressive tumor.
But Henrietta Lacks' story did not end with her death.
A portion of her tumor—the slices the pathologist had ex-
amined that February—was eventually passed on to a re-
searcher at Johns Hopkins named George Gey, who was in-
terested in how viruses, particularly the polio virus, grow in
human tissue. To carry out his studies he needed human cells
that could be grown in vitro. Gey was one of the leaders in
the emerging field of human cell culture, but his successes so
far had been marginal at best. Like others — anticipating
Hayflick's later studies—he found that human cells put into
culture would grow for awhile and then stop, which made
experiments with viruses very difficult. Experiments with a
particular cell line would yield tantalizing information about
viral growth or other properties, and then the line would dis-
appear. The virus would have to be passed to a new cell line,
often from a different tissue source, and almost certainly
from a different person. The virus might or might not be-
have in the same way in the new cells.
94
FROM SEX TO DEATH
Gey took the biopsy samples of Henrietta Lacks' cervi-

cal tumor back to his lab and began trying to grow cells from
them in vitro. As was his usual practice with human cell sam-
ples, he identified them by the first letters of the donors first
and last names: in this case, HeLa. Little did he imagine that
this name would survive not only Henrietta Lacks but him-
self and most of his coworkers.
After a week or so in culture, it became apparent that
these were very unusual cells. They grew vigorously, required
constant feeding, and had to be thinned out frequently to
prevent overcrowding in the culture dishes. Viruses loved to
grow in them. Everyone in the lab was delighted. Here at last
was a stable human cell line that could be used to study dis-
ease-causing viruses. There was some nervousness about the
fact that this was a tumor cell line, and thus possibly "not
normal." Would the results obtained with such a cell line be
applicable to normal cells? Comparisons of information ob-
tained with HeLa cells with previous results in the laborato-
ry apparently reassured the researchers. Investigators inter-
ested in other aspects of human cell biology asked for
samples of Gey's new HeLa cells; invariably, they seemed to
work beautifully. HeLa cells appeared to be ideally suited to
the study of a wide range of biomedical questions.
Soon HeLa cells became the most heavily used human
cell line in the world. They were distributed to researchers in
virtually every country, including (in the interests of detente)
various republics of the Soviet Union. HeLa cells were even
sent into space aboard the Discoverer 17 satellite. This wide-
95
spread proliferation eventually led to a minor scientific scan-

dal, and a major research problem. While delighted to use
HeLa cells in their studies, many researchers also continued
trying to grow other human cell lines from other tissue
sources — liver, kidney, or heart, for example. Such cell lines
were considered important because of the tissue-specific
properties they presumably possessed. But almost every lab
also grew HeLa cells, which were so much more vigorous and
aggressive than other cell lines that if even one single HeLa
cell somehow got into a culture of another cell type, the
HeLa cells would quickly take over, crowding the other cells
out. This apparently happened quite often. In 1966, Stan
Gartler, a geneticist at the University of Washington, tested
a number of human cell lines supposedly of different tissue
origins, and showed that the majority of them were in fact
HeLa cells. This was a major setback for researchers all over
the world who had already published, collectively, hundreds
of scientific papers based on the presumed properties of
heart cells or liver cells. In fact most of the cells they were de-
scribing were HeLa cells. The researchers were not amused.
This story illustrates once again the principle stated ear-
lier: death is not an automatic corequisite of life. HeLa cells,
and other human tumor cell lines that have since been es-
tablished, behave exactly like primitive single-cell organisms.
They proliferate asexually by simple fission. Give them un-
limited food and oxygen, thin them out periodically to pre-
vent overgrowth, and they will live indefinitely. Their "clock"
is perpetually reset; they do not senesce and die. Like germ
96
FROM SEX TO DEATH
cells, they are potentially immortal. The number of HeLa

cells in the world today—all of which still contain within
them the DNA hologram describing Henrietta Lacks — is im-
possible to estimate. If properly fed and cared for, HeLa cells
double at least once a day. As of the end of 1994, HeLa cells
had been around for over 15,000 days. Each cell put into
culture in 1951 could theoretically have produced 215'000
progeny. Such figures, even when accidental loss and pur-
poseful destruction of cells through the years is taken into
account, defy comprehension. But beyond any shadow of a
doubt, the DNA blueprints for creating a Henrietta Lacks are
the most plentiful and widely distributed set of such in-
structions in the world today.
Human tumor cells appear to have reverted to that state
of initial grace granted to the first cells on this earth, poten-
tial immortality. Unfortunately, unless removed from the
body and cultivated in vitro like HeLa cells, they never enjoy
their newfound freedom for long; with their voracious ap-
petites and need for space to grow, they eventually kill their
hosts, and themselves in the process. An immortal tissue in
a mortal body is a recipe for disaster. Scientists have found
that cells infected with certain viruses may escape the curse
of senescence as well, and enter into perpetual youth and re^
newal. But these virally transformed cells too are a threat to
the health of their hosts, and thus eventually to themselves.
How do cancer cells do it? How do they turn off their
senescence clock and avoid ultimate programmed death?
The answer intersects in interesting ways with the loss and
97
conditional reacquisition of immortality in germ cells. As we

have seen, the early cells of the human embryo retain the im-
mortal property of their germ cell progenitors. At this stage,
the growing embryo is in fact growing without any regula-
tion and is dangerously similar to a tumor. But this unregu-
lated growth is quickly brought under control as the embryo
begins to differentiate. All of the cells suddenly become mor-
tal; a special subset of these mortal cells will differentiate into
germ cells at a slightly later stage, and reacquire immortali-
ty. How does this come about?
One of the things that happens during embryonic de-
velopment and differentiation is the gradual shutting down
of the genome (the term used to refer to the entire collection
of DNA sequences scattered along all of the chromosomes).
Germ cells and early embryo cells at or before the stage rep-
resented by ES cells appear to have what we might call an
"open genome": essentially all of the genes of the genome are
open and accessible, ready to contribute to the various struc-
tural and functional components of the new individual. As
differentiation proceeds, however, the various cells of the em-
bryo begin to shut down entire blocks of genes, committing
themselves thereby to become only the types of cells speci-
fied by the remaining "open" DNA. Different cells leave dif-
ferent portions of their genomes open; the particular set of
genes remaining in the open state is what gives each cell type
its unique properties. Developing embryonic cells thus trav-
el along different pathways, but they all proceed from totipo-
tency to pluripotency (having a limited potential for further
98
FROM SEX TO DEATH
development), and eventually to become single, specific cell

types with very limited gene expression and no potential for
further or alternate development. A kidney cell, once fully
differentiated, no longer has the capacity to become a lung
cell; a brain cell can never become a blood cell. All of the
genes that were originally present in the open genome are
still physically present in every fully differentiated cell, but
in each such cell the vast majority of the genome is in a great-
ly repressed and inaccessible state.
It is during this transition from totipotency to the final
differentiated state that the embryonic cells become mortal.
The potential for future cell division is sharply curtailed and
in most cells will eventually disappear, and the process of
senescence begins. Understanding how this takes place, and
how it may relate to cancer, is one of the most active areas of
contemporary biological research. The current best guess is
that in fact the program for limited cell division and senes-
cence is present and operational even in germ cells and early
embryo cells, but that it is effectively neutralized by death re-
pressor genes whose products interfere with the senescence
program and the limits placed on proliferation.
Under this scenario, there would be sets of genes—we'll
call them death genes—whose expression initiates senescence
and loss of the ability to replicate chromosomes, leading
eventually to death of the cell. (These would be the genes ac-
quired by certain cell lines in the evolutionary "gain of func-
tion" event described earlier.) In open genomes, like those
found in germ cells and early embryo cells, the death repres-
99
sor genes are fully functional, allowing uninhibited cell divi-

sion and blocking senescence; as long as these genes are ex-
pressed, the cells are effectively immortal since the senes-
cence program cannot operate. As the cells begin to
differentiate and turn off large blocks of genes, the death re-
presser genes are among the first to be turned off. The death
genes themselves are never fully shut off. Again, as we saw
earlier in a different context, death is the default state. Tumor
cells appear to have found a way to turn some or all of the
death represser genes back on, or to turn the death genes off,
and to a greater or lesser degree mimic germ cells. In fact the
majority of tumors show almost no signs of cell specializa-
tion; they either have "de-differentiated," or have arisen from
a small pool of cells within each tissue that show limited de-
grees of differentiation.
One of the events contributing to senescence, and ulti-
mately to the activation of programmed cell death, is very
likely the accumulation of mutations in somatic-cell DNA, to
a point where the DNA begins coding for too many faulty
structural or functional proteins. Somatic cells appear to be
set up with monitoring equipment that allows them to know
when damage to DNA is approaching the critical point; when
this point is reached, the death genes become active and the
cell is instructed to commit suicide. As pointed out earlier,
germ cells and early embryo cells express high levels of DNA-
repair enzymes, which would prevent accumulation of DNA
mutations in the first place. These enzymes would thus be
candidates for products of death represser genes. (However
1OO
FROM SEX TO DEATH
not all tumors that escape control of cell replication acquire

the enhanced levels of repair machinery necessary to keep
their DNA and chromosomes normal; many tumors have
highly abnormal chromosome structures and mutant genes,
as do fibroblasts kept for long periods of time in culture. The
truly successful tumors, however, clearly have acquired
enough of the germ-cell-like state to keep their DNA and
chromosomes in good working order.)
Recently, cancer researchers have begun to focus atten-
tion on a structure we encountered in the last chapter—the
chromosomal telomeres. Recall that when eukaryotes lin-
earized their previously circular chromosomes, they had to
cap the ends with telomeres to keep them from recirculariz-
ing, or from sticking to each other end to end. Telomeres are
themselves made of DNA, but in a form less sticky than ordi-
nary DNA. When cells divide, the telomeres are not repro-
duced along with the rest of the DNA in the chromosome;
they are added anew at the chromosome tips after each
round of cell division, using an enzyme called telomerase.
Researchers had noticed that as individuals age, the
telomeres at the ends of their chromosomes gradually get
shorter. The same thing can be seen in fibroblasts grown in
culture; fibroblasts taken from a young person start out with
long telomeres, but as the cells age in vitro, the telomeres
grow shorter until they almost disappear. Fibroblasts isolat-
ed from progeric children have extremely short telomeres. It
is believed that as telomeres shorten and disappear, chromo-
some ends begin to stick together, making chromosomal
1O1
replication of DNA (and hence cell proliferation) virtually im-

possible. There had been suggestions that telomere shorten-
ing might be related to senescence, but it was not obvious
whether it was a cause or an effect. Recently, however, re-
searchers took a closer look at HeLa cells which, as we have
seen, have gone through a huge number of cell divisions
since they were first put into culture forty-five years ago. To
everyone's surprise, HeLa cells have long, healthy-looking
telomeres, typical of those found in germ cells and in the
cells of very young individuals. They also have very high lev-
els of telomerase. This is a condition found in many long-
term human tumor cell lines and again, there is a strong re-
semblance here with germ cells: both germ cells and early
embryo cells have high levels of telomerase activity. ES cells
also have very high levels of telomerase, and maintain their
telomere length through an indefinite number of cell divi-
sions. But once the early years of growth and increase are
over, telomerase activity declines and the telomeres gradual-
ly shorten. Telomerase may thus be another good candidate
(at least in humans) for one of the death represser genes.
As for the death genes themselves, a number have been
identified, but one of the most interesting continues to be a
gene coding for a protein called p53. This gene plays sever-
al important roles. For example, when cells have been irra-
diated to a point where their DNA is damaged, the p53 gene
is activated and induces the cell to commit suicide. The p53
gene also prevents cells from proliferating when they should-
n't: it prevents them from becoming cancerous. When nor-
1O2
FROM SEX TO DEATH
mally quiescent cells try to enter into active cell division, the
p53 gene is again turned on, and the cells undergo apopto-
sis. Not surprisingly, mutations in p53 (which render it func-
tionless) are the most common mutation seen in human can-
cer; cells that have lost p53 often begin to divide without any
control. Supporting this clinical observation is the fact that
mice that have had the p53 gene knocked out have extreme-
ly high spontaneous cancer rates. Finally, p53 appears to be
involved in the normal senescence of human cells. When
human fibroblasts are placed into culture, as we have seen,
they eventually age and die by apoptosis. But if the p53 gene
is somehow silenced, senescence is greatly retarded and a
large number of the fibroblasts actually become immortal-
ized— they become like HeLa cells.
The correspondence between early embryonic cells and
tumor cells has fascinated researchers for many years. A great
deal has been learned about the death of cells by studying
cells that have somehow evaded it. And it is inescapably true
that the death of a human being begins with, and is ulti-
mately entirely explainable by, the death of individual cells.
The two deaths cannot be separated from one another; they
are the same death, whether we write on the hospital chart
that death came from a "heart attack" or "cancer" or simply
"old age." Yet as we have seen death is not, a priori, a re-
quirement of life. Somatic cells — and thus the need for
compulsory somatic cell death — arose only after DNA began
making copies of itself that would be used for purposes other
than reproduction. For humans this means that once a rea-
1O3
sonable number of our germ cells have been given a chance

to impart their reproductive DNA to the next generation, the
rest of us — our somatic selves — becomes so much excess
baggage. That is the biological origin of senescence and
death.
From a human point of view, it is our somatic selves —
embedded in which are things like mind, personality, love,
will—that we cherish most and that define us, to ourselves
and to others. We think of reproduction as only one of many
activities we can choose to engage in. Perhaps this is not sur-
prising, since it is a point of view arising in the somatic part
of ourselves — in our minds. We have used our minds to in-
vent complex belief systems to explain death. None of these
paint a picture of ourselves as excess baggage; none cast us
simply as tools for transmitting DNA. Yet when we trace the
origin of our death beyond mind and belief, to its true be-
ginnings — the death of individual cells — we come to a
rather harsh and unflattering conclusion: the irrelevance, in
the grander scheme of the universe, of our somatic selves. No
wonder belief so often triumphs over reason.
1O4
5
A Hierarchy of Cells:
The Definition of
Brain Death
The Brain is just the weight of God.

—Emily Dickinson
Let us turn once again to our patient, who we left

in the back of an ambulance speeding toward a hospital
emergency room. The paramedics continued to provide oxy-
gen and to monitor his vital functions closely during the
ride. Fortunately the morning traffic was still light; they
reached die hospital in just under five minutes. When he was
brought into the ER, he was still unconscious. His heart was
1O5
beating regularly, but more slowly than it should. His breath-

ing appeared relatively normal.
Immediately upon his arrival in the hospital, steps were
taken to decrease the possibility of further damage to his
heart. (All the damage is not done at the moment of the at-
tack; it evolves slowly over a period of several hours.) He was
connected to a more sophisticated heart monitor (EGG), and
to a hospital source of pure oxygen. A second i.v. line was
started to facilitate drug and nutrient delivery. Immediate
measures were taken to decrease the demands placed on his
heart. He was given clot-inhibiting agents to prevent further
blockages in the arteries feeding the heart muscles, and lido-
caine to prevent irregular heart rhythms from developing.
Blood samples were drawn and sent to the laboratory for
analysis to help determine the precise extent of the damage.
Dead cells, as we have seen, release their contents into the
lymph, which eventually makes its way back into the blood-
stream. The presence in the blood of substances normally
found only inside healthy cells can tell the clinical chemist
which cells have died, and approximately how many and
how long ago.
Our patient's slow heartbeat (bradycardia) worried the
emergency room physicians; atropine and dopamine were in-
troduced through his i.v. to speed up his pulse. He was mon-
itored very closely; this is a risky procedure. On the one hand
his doctors wanted to reduce the load on the heart, but the
potential danger of a feeble pulse is much greater, because it
slows delivery of life-giving oxygen to the tissues, including
1O6
A H I E R A R C H Y OF CELLS
the brain. He was stable enough after an hour or so to be

moved to the coronary intensive care unit. Physiologically he
is now relatively stable; but he has not regained conscious-
ness, and this does not bode well.
As we stand here in his room and watch him lying in his
bed, he looks quite normal in many ways. His hair is a little
matted, and he seems sunken back into the mattress. The
events of the past few days have clearly taken a physical toll.
But he is breathing well on his own now, and he is warm to
the touch. A physician shines a light into his eyes, and his
pupils contract normally. He jerks away in response to
painful stimuli. When food is delivered through a gastric
tube or an i.v. line, he digests it and sends the nutrients out
through the bloodstream to his cells and tissues, which effi-
ciently use them in combination with the oxygen his breath-
ing provides. His kidneys process and excrete the wastes pro-
duced by his cells.
On the other hand, he still has not opened his eyes. He
has no knowledge of the room he is in, or of the people who
come and go to minister to him, or indeed of his very exis-
tence. He is in a deep coma. The initial laboratory tests, bed-
side examinations and electroencephalogram (brain wave)
patterns suggest the possibility that he may be apallic: that
the cortex of his brain, which is highly sensitive to oxygen
deprivation, may no longer be functioning, but that his
brainstem, the less oxygen-sensitive encephalon, is still alive.
All of the responses described above, such as temperature
control and pupillary contraction, are actually involuntary
1O7
ARS
Figure 7. Major anatomical divisions of the brain. The cerebral cortex (Cx)
is the region of the brain housing those functions most associated with
"human-ness": thinking, memory, awareness of oneself and of the
environment. The thalamus (T) is like an air traffic control tower; it sorts
out, coordinates and integrates the various sensory inputs coming into the
brain. The hypothalamus (H) and. pituitary gland (P) control the brain's
hormonal connection with the rest of the body. The cerebellum (Cb) helps
us to keep our sense of balance and physical coordination in relation to the
world around us. The brainstem, or encephalon (En), controls basic body
functions (heart rate, breathing) as well as reflexes (pupillary reflex,
gagging, swallowing). It also contains the origins of something called the
ascending reticular activating system (ARS), which regulates alertness and
wakefulness versus sleeping.
reflexes controlled by the encephalon; they require no high-

er brain function or coordination.
If he does not regain consciousness in the next several
days — and particularly if he remains comatose—the likeli-
hood will increase that he has indeed lost all higher cortical
functions. It is possible he may emerge from coma but still
not recover consciousness; he could enter a persistent vegeta-
tive state (PVS). More tests will have to be done, but it is a pat-
tern the nurses and physicians in the coronary icu have seen
all too often. In spite of heroic efforts by his wife and by the
responding life-support teams, parts of his brain may simply
have been deprived of oxygen for too long a time. The diffi-
culty in reestablishing breathing may well have been the crit-
ical factor, but it will be impossible to know.
We will return to see how our patient finally fares in
Chapter Seven. He will be moved shortly to the general in-
tensive care unit, where he will be watched closely over the
coming days. A clear diagnosis will at a minimum take sev-
eral weeks of observation and testing. At some point the hos-
pital staff will have to reach a conclusion about the state of
their patient's brain function, and report that conclusion to
his wife. In the meantime, we should begin to consider the
fine line in cases like this between life and death. It is very
complex; it is the point at which the death of a cell and the
death of a person would appear to diverge.
At first glance our patient seems very much alive.
However, if enough of his brain were to be judged com-
pletely nonfunctional he could in fact be pronounced dead,
1O9
regardless of how lifelike he might seem. But how much of

his brain must be dead for such a declaration? What if his
brain is not completely dead, but he never regains con-
sciousness? Is he then really alive? How and by whom are
such decisions made?
The current medical standard for deciding whether
someone is legally alive or dead in cases like this is what is
called the brain-death standard. The impetus for establishing
such a standard arose from a variety of needs created mostly
by advancing technology, precisely the type of technology
that has kept our patient alive for the past seventy-two hours.
Prior to about 1950, declaration of death was relatively un-
complicated, and basically any physician could declare some-
one dead. The criteria were vague, revolving around the
commonsense ideas that someone whose heart is not beat-
ing, or who is not breathing, is almost certainly dead. If the
physician was slightly off in his or her determination of an
exact moment of death, no matter. Anyone without a heart-
beat or unable to breathe would surely be dead in a matter
of minutes.
But with the advent of defibrillation and assisted-venti-
lation technologies, these standards could no longer be au-
tomatically applied. In an increasing number of cases, peo-
ple whose hearts were not beating, or who were not
breathing, could be resuscitated and maintained well past the
point where previously they would have been declared dead.
With dissemination of these technologies into the commu-
nity, through citizen education about CPR and, more impor-
11O
tantly, provision of paramedics with proper training and

equipment to deliver vital pre-hospital care, a significant
number of resuscitated individuals — perhaps as many as
twenty percent—now go on to a full recovery, literally back-
ing out through death's door.
The creation of a brain-death standard was also driven
by the need to define permissible conditions for removing
organs for transplantation. The technologies for sustaining
biological functions in persons unable to maintain a heart-
beat or breathing on their own evolved largely in parallel
with the technology to harvest and successfully transplant
vital organs. From legal and ethical viewpoints, as well as
for purely medical reasons, both transplant surgeons and
hospital administrators wanted the moment of death, par-
ticularly in the case of artificially maintained patients, clear-
ly defined. All organs begin to degenerate very rapidly upon
death, and need to be removed from a dead donor as quick-
ly as possible if they are to function in a living recipient. So
even (or perhaps especially) when a patient maintained on
life-support systems has previously expressed a willingness to
donate organs upon death, someone has to declare the exact
moment when death has occurred and the organs can be har-
vested. An increasingly litigious public has driven many hos-
pitals and transplant surgeons to seek the protection of the
law in borderline cases.
And last, but not least, remember that at the precise mo-
ment a person is declared dead, his or her legal and moral
rights as a person cease completely. Health insurance to hos-
111
pitals and physicians stops, and life insurance must be paid

to beneficiaries. The precise moment of death may have im-
portant implications for a wide range of legal issues related
to survivorship as spelled out in wills, and for those who in-
herit both the assets and the liabilities of the deceased. This
may be especially critical when both a husband and a wife,
each with separately defined lines of succession and inheri-
tance, are critically injured and near death.
In 1968 a group of physicians met at Harvard University
to establish new criteria for declaring a person dead on the
basis of loss of control by the brain of circulation and breath-
ing, and loss of integration by the brain of other critical bod-
ily functions. They proposed that, in the absence of specific
conditions such as drug intoxication or hypothermia, a per-
son who is judged irreversibly comatose, is unable to breathe
unaided, and has no neurological reflexes or electrical activ-
ity in the brain is dead. These criteria were discussed and re-
fined over the next dozen years or so. In 1981, the President's
Commission for the Study of Ethical Problems in Medicine
and Biomedical and Behavioral Research, in collaboration
with a variety of professional health organizations and the
National Conference of Commissioners on Uniform State
Laws, crafted the Uniform Determination of Death Act
(UDDA). The UDDA was formulated in an attempt to coordi-
nate the independent efforts of the various states and feder-
al jurisdictions struggling to formulate a definition of death
consonant with the new technologies. The UDDA quickly
112
became the basis for legislation defining clinical death in all

of the fifty states.
The UDDA proposed two fundamental criteria of death.
First, an individual with irreversible cessation of circulatory and
respiratory function is dead. This is just a restatement of pre-
vious standards for death, reaffirming their general validity.
Second, an individual with irreversible cessation of all func-
tions of the entire brain, including the brainstem, is dead.
Again, complicating conditions such as shock, hypothermia,
drug intoxication, and age less than one year were cited as re-
quiring special examination to establish true death.
Although these criteria initially satisfied a majority of
medical personnel, legal specialists, and most medical ethi-
cists, some concern has been expressed in recent years about
the appropriateness of the UDDA definition of brain death.
The primary concern relates to the requirement for "whole
brain" death. Although explicitly stated only in the second
of the two definitions, this requirement is actually embed-
ded in the first as well. Respiratory function (breathing) is
regulated by the encephalon, the most primitive element of
the brain, through its control of the diaphragm and chest-
wall muscles. The brainstem also controls a variety of other
reflex reactions mentioned earlier, such as body temperature,
blood pressure, and the pupillary and gag reflexes. Without
brainstem function, a person cannot breathe unaided, and
this has become the most important criterion for determin-
ing brain death under UDDA guidelines. Various tests involv-
113
ing withdrawal of artificial respiration and observation of au-

tonomous breathing have been defined. If a person cannot
breathe unassisted after several well-monitored attempts, he
or she can be declared dead, and no one would much argue
with the decision. Even with a ventilator to assist breathing,
such patients rarely survive more than a few weeks, because
of the dependence of the heart and blood pressure on at least
some brainstem function. However, in a few cases biological
functions can be maintained for longer periods. In 1993, a
California woman declared brain-dead was found to be
in her fifth month of pregnancy; she was maintained on
life-support systems for three months until the baby could
be delivered by caesarian section. The baby did well; the
mother was disconnected from life support at the end of the
delivery.
But it is possible to breathe without mechanical aid, and
to display a limited number of reflex reactions, with only en-
cephalic brain function. The pumping function of the heart
is largely independent of the cortical regions of the brain. If
the heart survives the damage inflicted during myocardial is-
chemia and the resulting infarction, it can get along fairly
well on its own. According to UDDA criteria, a person with
intact encephalic brain function and a beating heart is not
dead. Thus our heart-attack patient, if he truly is in a persis-
tent vegetative state with intact brainstem function, is still
legally alive; he cannot be declared dead by the hospital staff.
The persistent vegetative state was rare just a few decades
ago, but a number of factors have intersected to produce an
114
estimated 10,000 to 20,000 adult PVS patients at any given

time in hospitals and nursing homes throughout the United
States, in addition to perhaps half that many PVS children.
This increase is largely a consequence of the technology and
procedures that have brought our patient to his present sit-
uation; even ten years ago he would not likely have survived
his ordeal. The term "persistent vegetative state" itself was
not well defined, medically or legally, until just a few years
ago. Doubtless some of the apparent increase in the number
of PVS patients is a matter of better understanding among
health professionals of just what PVS is, and thus more accu-
rate recording of diagnoses. In the past PVS was often con-
fused with coma; the major difference between the two states
is that persons in a coma never open their eyes, whereas PVS
patients show alternating patterns of sleep and apparent
"awakeness." In neither case does the individual involved
have any awareness of the surrounding world; the PVS patient
and the comatose patient are both completely unconscious.
Truly comatose patients have a very poor prognosis;
eighty-five percent die within four weeks. Those who do not
regain consciousness within this time rarely survive a year.
The major cause of death is lung infection; comatose pa-
tients do not have well-developed gag, swallowing, and
coughing reflexes, which are important in keeping infectious
agents out of the lungs. Although such patients retain some
degree of brainstem function, they have lost portions of the
brainstem controlling critical functions such as the sleep/
wake cycle and gagging.
115
Patients may enter a true persistent vegetative state for a

variety of reasons, but the major ones are severe head trauma
and temporary loss of blood to the brain (transient total brain
ischemia), usually following a heart attack. Patients entering
PVS because of brain ischemia have only a slightly better
long-term outlook than truly comatose patients. Roughly
ten percent will recover from PVS within the first month or
so after diagnosis, but three out of four of these will have
moderate to severe neurological disorders that may shortly
prove fatal. Recovery from PVS after the first month is very
rare, and is almost always accompanied by severe neurolog-
ical deficit. However, the persistent vegetative state itself, as
the name implies, can last much longer than true coma. The
average survival time for PVS patients is around three years;
the longest surviving PVS patient "lived" forty-one years.
Death normally results from infection of the lungs or blad-
der, or from cardiorespiratory failure. All medical authorities
agree that persons in a persistent vegetative state have no
ability to experience pain or discomfort. The fact that they
appear to be awake, and sometimes display eye and limb
movements, may make this hard to accept, especially for
family members. But the experience of pain as a sensation
absolutely cannot occur in an unconscious person, and PVS
patients are absolutely unconscious.
Patients in a persistent vegetative state are the principal
focus of the current debate about brain death. Many med-
ical and legal experts feel that the presently framed require-
ment for whole-brain death is too restrictive, and that the
116
functions regulated by the brainstem, while important to the

biological survival of the organism, have little to do with
what it means to be a live human being. "Human-ness," they
would argue, has to do with a particular self, a particular per-
sona, that makes each of us different. When we say that "so-
and-so" died, we think of the way that individual moved and
thought and talked and acted, not of his or her ability to
swallow or narrow the pupils of the eye in response to light.
We don't say an individual's body died. A human personali-
ty is characterized by a unique set of values exercised with a
particular brand of reason and judgment that leads to a high-
ly individualized response to the surrounding world. It is a
way of seeing that world, of thinking about it and respond-
ing to it—of being in it—drawing upon a highly idiosyn-
cratic collection of memories, of reflections on joy and on
suffering. These are all functions of the cerebral cortex, as far
as we know. If a person has lost all this, irreversibly and irre-
trievably, but can still gag and swallow, some would question
seriously whether that "person" is still alive. None of the
qualities we associate with being human reside in the en-
cephalon, any more than they reside in the kidney or the
liver or the spinal cord. Why then is the state of the en-
cephalon the defining feature of human death? What if the
encephalon itself were completely lost, but its functions were
taken over mechanically—if such a person's higher cortical
functions were still intact, would we be willing to declare
that person dead? To some extent, this has happened; the
pregnant "brain-dead" woman referred to earlier was kept
117
biologically functional by supplying some of the chemicals

ordinarily supplied by her damaged encephalon.l Yet, once
the baby was delivered, these treatments were stopped and
the ventilator was removed. Technically, it was argued, these
treatments did not kill her, since she was already dead.
Proponents of a higher-brain definition of death thus
argue that we should focus on the death of the person and not
on the death of the organism. From this point of view, it
ought to be permissible to define death as the irreversible loss
of higher-brain (cortical) functions—specifically, conscious-
ness and cognition — rather than insisting on loss of whole-
brain function. Such distinctions are uniquely human. They
do not arise in discussions of the death of single-cell organ-
isms, or even of multicellular animals. Death of multicellu-
lar organisms, as we have seen, arose from the need to dis-
pose of excess DNA and the cells that house it. Somatic cells
eventually die — all of them — while germ cells—some of
them — gain immortality through passage into another
being. In other animals, when all of the somatic cells are
dead, we consider the organism dead, period; this is a defin-
ition that we apply uniformly across all five kingdoms of liv-
ing things. But human beings have introduced a new notion
1 The necessity to use a term such as "biologically functional" is an indication
of how the adoption of acceptable terminology can lag behind the reality it
tries to describe. Brain-dead individuals (bodies?) kept from total somatic-cell
death by a combination of chemical and mechanical means have no status in
science, medicine, or the law. Legally, they are dead; biologically, they are un-
defined.
118
into the biology of our own deaths—a hierarchy of somatic

cells. Even with the whole-brain definition of death as it now
stands, we make a distinction among somatic cells; for brain
cells are, in the end, just another kind of somatic cell. We say
that when the brainstem cells are dead, even if the vast ma-
jority of other cells in the body are kept alive by technology,
a "person" is dead. The implication is that someone with in-
tact brainstem function is alive. Yet in such an individual, the
very cells that define a human organism as a "person" — the
cells of the cortex—may be completely dead.
This redefinition of death along lines that apply
uniquely to human beings is just one of a number of issues
that disturb many who defend the whole-brain definition
of death. They ask themselves why such a redefinition
should be necessary. Death is a wide-ranging biological phe-
nomenon, and death in all other animals is defined simply
as total somatic cell death. It is unlikely that we would label
as dead any other organism whose heart still beats, whose
blood still flows. Why then do we need a special definition
of death for humans? To save money for insurance compa-
nies and hospitals? To make it easier to harvest organs for
transplantation? Death is a singular and sacred event in a
human life — ought we to be redefining it for reasons of
convenience or economy?
One of the criticisms of the whole-brain definition of
death has been that no one is quite sure what "whole-brain"
death means. The formulators of this concept obviously in-
tended it to mean that someone cannot be declared brain-
119
dead unless the brainstem, as well as the cortex, is dead. But

how much of the brainstem must be dead to meet this crite-
rion? Half? Three-quarters? Every single cell? How would we
prove that every single cell in the encephalon is dead? In fact,
it is rare that patients declared brain-dead under current
guidelines have demonstrably lost every single function of
the encephalon. And why stop there? The encephalon leads
directly into the spinal cord. Are there no functions even one
centimeter beyond the tip of the encephalon that we would
equate with life? If so, what is the basis for excluding them?
But defenders of the whole-brain concept put the ball
right back in their opponents' court. How much of the cor-
tex would have to be dead to define the death of a human
being? Half? Three-quarters? Every single cell? And how
would we prove that every single cell in the cortex is dead?
They argue that we simply do not know with certainty ex-
actly which life functions are attributable to which regions
of the brain. We do not really know whether or to what ex-
tent (although admittedly it would be small) some regions of
the encephalon may affect things like personality or memo-
ry or a sense of humor. And we have no way of determining
precisely how many cells in which regions of the cortex are
dead. If we do not know absolutely that the persistently veg-
etative patient is not alive, should we not err on the side of
life, however reduced its definition, however slim its possi-
bility?
In the end many people, including many eminent
bioethicists, are simply uncomfortable with declaring dead
12O
someone who retains any brain function. One of the

more recent and eloquent iterations of this position was set
forth by Dr. James Bernat, professor of neurosurgery at
Dartmouth Medical School:
. . . there is a clear conceptual distinction between the hope-
lessly brain-damaged patient in a persistent vegetative state, and
the patient who is dead. . . . It is counterintuitive to the con-
cept of death to imagine that physicians would have to observe
a patient for several weeks or months before they could deter-
mine if he was dead. .. . Practical conflicts arise when we con-
sider declaring dead, patients who are in persistent vegetative
states. . . . Should they be buried or cremated while still in pos-
session of motor, sensory, and autonomic behaviors? If not,
should they first be given an injection of high-dose barbiturate
to abolish these behaviors? Why should such an injection be
necessary if they are already dead?
It may be that we as a society will never be able to

define the exact and true moment of death, and perhaps we
shouldn't try. First of all, it is unlikely that a pluralistic,
multicultural society such as ours will ever arrive at a defin-
ition of humanness or personhood, or even life and death,
acceptable to all or even to a majority of people. The highly
emotional and long-standing debate about abortion indi-
cates clearly the difficulty of defining the moment when the
life of an individual begins. In the words of Robert Veatch,
professor of medical ethics at Georgetown University and
one of the most forceful critics of the whole-brain definition,
"The determination of who is alive — who has full moral
121
standing as a member of a human community — is funda-

mentally a moral, philosophical, or religious determination,
not a scientific one." Similar sentiments are expressed by at
least some defenders of the whole-brain definition of death,
like bioethicists Jeffrey Botkin and Stephen Post: "the mo-
ment of death is not a specific physiologic event amenable
to scientific determination. Rather, it is a moment defined
by philosophic concepts — concepts that speak to what it
means to be alive. Since such philosophic contentions defy
objective proof, the moment of death must be seen as an
event fixed by social consensus."
And yet we have a problem on our hands, a problem
generated by technology that we as a society have created. It
is a problem that we as a society must try to solve. Thousands
upon thousands of patients are now suspended in PVS. Such
individuals far outnumber the fortunate few whose lives are
actually restored to normal by our resuscitative technologies,
and their ranks increase daily. Maintaining them can some-
times place a devastating emotional burden on their loved
ones, and a crushing financial burden on society as a whole.
What are we to do?
This dilemma may be eased by the current trend toward
giving more weight to advance directives written by the
patient, or, when there are no directives or the patient is in-
competent, recognizing the rights of an appropriate surro-
gate (usually a first-degree relative or legal guardian) to make
such decisions. Advance directives (sometimes called "living
wills") that clearly express the wishes of an individual not to
122
be maintained in a persistent vegetative state are now hon-

ored in all fifty states. In fact, a federal law that went into ef-
fect in December 1991 requires hospitals to ask patients
upon admission whether they have completed an advance di-
rective, and if not, to assist them in doing so. Of course this
is of no help to patients who are incompetent at the time of
admission — those in a coma, for example, or individuals
who are severely retarded. Most states also recognize in some
form or another the right of defined surrogates to make
treatment decisions on behalf of an incompetent PVS patient
who has not made out an advance directive.1
The trend toward surrogate decision-making has evolved
through a series of legal decisions made in recent years as
doctors, patients, and hospitals have struggled to understand
the implications and boundaries of the Uniform Determina-
tion of Death Act. This dialog between our medical and legal
systems began in earnest even before the UDDA was formu-
lated, with the landmark case of Karen Ann Quinlan. In
April 1975 the twenty-one-year-old Quinlan collapsed at a
party after consuming a moderate amount of alcohol while
she had an alcohol-incompatible prescription sedative in her
1
Although virtually all hospitals welcome and recognize living wills and
durable powers of attorney identifying surrogate decision-makers, a recent
study in New York and California found that a large majority of elderly per-
sons who had made such documents failed to communicate this information
to either their health-care providers or their next of kin. Anyone with health
documents of this kind is urged to make their existence as widely known as
possible — to the family doctor, to immediate relatives, and even to friends.
123
system. Shortly after she lost consciousness, her heart

stopped beating and she ceased breathing; her friends ad-
ministered CPR as best they could while waiting for help. Her
heart and breathing stopped again after help arrived, and CPR
was adminstered again, this time by a policeman. The total
period of time without spontaneous respiration has been es-
timated at fifteen to thirty minutes. At the hospital her pulse
was stabilized, but she remained unable to breathe on her
own and was placed on a respirator. Spontaneous breathing
returned within an hour or so but was irregular, and she was
kept on a respirator that monitored her breathing pattern
and provided assistance as needed. She never regained con-
sciousness. Detailed testing over the next several months sug-
gested she was in a persistent vegetative state. Those attend-
ing her were of the opinion that she would not recover, and
this was explained to her parents, Joseph and Julia Quinlan.
After a few more months with no signs of improvement, her
parents asked that she be taken off the respirator. She had
gradually become more dependent on mechanical assistance
for breathing, and it was assumed that without it she would
die peacefully in a fairly short time.
The Quinlan family's request came at a time when the
debate about brain death was just beginning, and at a time
when the right of surrogates to participate in decision-mak-
ing was largely untested. Her ability to breathe on her own
sporadically did not entirely fit the definition of whole-brain
death, and the hospital and Quintan's physicians were not
sufficiently sure of the evolving guidelines to honor the fam-
124
ily's request. Her parents then applied to the Superior Court

in New Jersey, their state of residence and the state in which
their daughter was being treated. The court ruled that there
was no basis in law to compel a medical facility to remove a
patient in her medical condition from a respirator. The par-
ents appealed this ruling to the New Jersey Supreme Court,
whose chief justice at the time was Richard Hughes, a for-
mer governor of the state.
Although about to leave for a trip to Japan, Hughes
agreed (at his wife's urging) to hear the case immediately. In
a 1976 opinion written almost entirely by him, the New
Jersey Supreme Court issued a decision that has become the
starting point for almost all subsequent law in this area.
Discarding other possible bases for granting the family's re-
quest, Hughes generated a compelling case based on the con-
stitutional guarantee of an individual's right to privacy.
Hughes reasoned, as had others before him, that the right to
privacy includes the right to exercise control over one's own
life. The state also has a well-recognized interest in the life of
each of its citizens, and may take steps to preserve and pro-
tect life that may at times interfere with the rights of the in-
dividual. But here Hughes departed from previous interpre-
tations of the state's interest in such matters. He argued that
as the power of the state — and by inference medicine and
medical technology—to preserve and protect the life of an
individual diminishes in the course of a natural deteriorative
process, so too does the power of the state to interfere with
that individual's right to control his or her own destiny. And
125
breaking even further with precedent, he argued that when

an individual is incompetent because of the deteriorative
process to exercise this right of control, the right can be ex-
tended to a competent surrogate decision-maker. Moreover,
Hughes advanced the notion that the appropriate surrogates
in such a case should be the family, not the courts or the
medical establishment.
Following this decision of the New Jersey Supreme
Court, the hospital charged with Quinlan's care honored her
family's request to remove her from the respirator. She was
gradually weaned from mechanically assisted breathing over
a period of a month or so, and then moved to a nursing
home. She did not, as expected, die shortly thereafter; in fact
she lived for almost another ten years, although she never re-
gained consciousness. She continued to receive food and
water through tubes. She died in June 1986 of a combina-
tion of pneumonia, endocarditis, and meningitis. An autop-
sy was performed with the family's permission, and her brain
was preserved for further study. The results of that long and
careful study were finally published, with the family's per-
mission, in the May 1994 issue of the New England Journal
of Medicine. It had become clear even before her death that
hers was not a classic case of loss of brainstem function, since
she retained the ability to breathe on her own. From the loss
of all higher cognitive functions, it was presumed that she
had suffered cortical damage as a result of oxygen depriva-
tion. In fact, the most severe damage was in the area of the
thalamus (see Figure 7 on page 108), which sorts out in-
126
coming signals and routes them to appropriate parts of the

brain. The cortex was relatively undamaged. This finding
was a great surprise to the medical community, and neurol-
ogists are now reassessing their models of the neuroanatom-
ical basis of human consciousness. It reinforces the con-
tentions of a number of bioethicists that we do not yet fully
understand which life functions are associated with which
regions of the brain. The pathologists' description of Karen
Quinlan's brain will certainly alter the content of debates
about possible higher-brain definitions of death.
The Quinlan case is the foundation on which a great
deal of our thinking about a patient's "right to die" is based,
although subsequent court decisions have also helped guide
us in this delicate matter. The U. S. Supreme Court has de-
clined to provide definitive guidelines, preferring to leave
these matters to state courts. Even the state courts have gen-
erally been reluctant to intervene in a decision that, follow-
ing the reasoning in Quinlan, is considered best resolved by
the patient, or the patient's surrogate, and the doctors in-
volved. Only when the parties simply cannot agree among
themselves have the courts stepped in. Each of these cases has
helped society to refine its thoughts on this issue. One case
involved Claire Conroy, an eighty-four-year-old woman who
suffered from brain damage essentially equivalent to PVS. She
was living in a nursing home, and had been for some time
completely unaware of her surroundings, with minimal brain
function and no cognitive ability at all. In 1979 her only sur-
viving relative, a nephew, was appointed her legal guardian.
127
In 1982, after a long series of degenerative medical episodes,

Conroy became permanently dependent on a nasogastric
feeding tube. The nephew felt that continued treatment was
incompatible with her dignity as a human being, and asked
that the feeding tube be removed—essentially, that she be
allowed to die in peace.
The hospital, while fully aware of the Quinlan decision,
was not at all certain that withholding food and water would
be viewed in the same light as removing a patient from a ven-
tilator. Quinlan, after all, had been maintained on just such
a feeding tube for nearly ten years. The hospital refused the
nephew's request, and he appealed to the courts. The origi-
nal trial court agreed with the nephew and ordered the hos-
pital to comply with his request as Conroy's legal guardian.
The case was appealed, and the initial ruling was reversed by
an appellate court. The nephew was preparing to take the
case to the state supreme court (again in New Jersey) when
Conroy died. He decided to proceed anyway, as a contribu-
tion to clarifying the law in such cases. In its 1985 decision,
the court made two important points which have generally
been incorporated into subsequent rulings. First, the right of
a patient or a surrogate to make a decision about withdraw-
ing any treatment, when that treatment no longer serves a
useful end, does not necessarily have to be founded on the
constitutional guarantee of privacy, but can be extracted
from "the common law right to self-determination." This ac-
tually strengthens a patient's rights in such matters, because
it interprets the right to die as a fundamental human right,
128
rather than a political right potentially subject to a court's in-

terpretation of the constitution. Second, the court ruled that
artificial delivery of food or water that substitutes for a pa-
tient's ability to eat and drink is a form of medical treatment,
just like a ventilator that replaces a patient's ability to
breathe. Therefore, removing tubes that deliver food and
water should be viewed in the same way as removing a pa-
tient from a ventilator. Patients have an inherent right to
refuse such treatment, and with appropriate safeguards this
right may be extended to their surrogates.
Do such decisions pave the way for courses of action that
may not be in the best interests of the patient? Could they
start us down the infamous "slippery slope" toward sanc-
tioned euthanasia? Many fear that they may, and we are right
to be cautious. But the record suggests that such fears may
be misplaced. Take the case of Helga Wanglie, an eighty-six-
year-old Minneapolis woman who had been in a persistent
vegetative state requiring ventilator support for just over a
year when the hospital sought the family's permission to re-
move her from the ventilator. The hospital felt that under the
circumstances continued treatment would in no way con-
tribute to the patient's welfare, and was therefore inappro-
priate. The patient's husband refused permission to withdraw
treatment, and the hospital went to court, asking that an in-
dependent surrogate be appointed for Wanglie. In July 1991,
the Minnesota court affirmed the husband's right to act as
Wanglie's surrogate, further consolidating earlier legal opin-
ions. But it also ruled that while it may be the duty of courts
129
to define and protect the rights of patients and surrogates to

make such decisions, courts have no jurisdiction over the
content of a surrogate's decision, as long as that decision is
one the patient might reasonably have made on his or her
own, and unless that decision can be shown to be clearly not
in the patient's best interest. The court ordered that having
clearly met this test, the family's wishes must be respected.
The issue of who should bear the financial cost of continued
treatment was never resolved; Helga Wanglie died of sep-
ticemia a few days after the court rendered its verdict.
And so, although significant differences among the
states remain, an emerging consensus has begun to shape the
interaction of doctors and hospitals with patients or their
surrogates. First and foremost, both the medical and legal es-
tablishments greatly prefer to see clearly written advance di-
rectives by the patient. Virtually no one will argue with these
anymore. In the absence of such directives, or when the pa-
tient is incompetent to provide such information at the time
of admission, first-degree relatives or legal guardians are
being granted increasing latitude and power as surrogates to
decide when treatment of hopelessly brain-damaged patients
should be terminated. A surrogate may act on knowledge of
what the patient would have wished, or failing that, may
make any considered decision the patient might reasonably
have made. The decision may be to continue or to discon-
tinue treatment; it is the ability to decide that is increasing-
ly being guaranteed; the content of the decision is not a chal-
lengeable issue. These types of actions are being taken with
13O
fewer and fewer references to the legal system; most of the

major questions have been addressed by the courts where
needed, and the medical profession seems more confident
that this approach is likely to be approved by society gener-
ally. Hospitals generally review this procedure to the extent
of validating the status of the surrogate, and the reasonable-
ness of the decision, but not beyond. An impressively large
number of medical experts and bioethicists are actively pro-
moting this trend, which in effect allows the patient to
choose his or her own definition of death.1
Unquestionably, dealing with the death of someone close
is traumatic, combining an enormous sense of loss with a
foreshadowing of our own mortality. In the case of a loved
one who has lingered in a persistent vegetative state, the trau-
ma may be partially offset by gradual accommodation and
acceptance of the inevitable, but it can also be heightened if
we have to be involved in the final decision that death should
be allowed to come, even when we know in our hearts that
that is what the patient would have wanted. If making this
decision is complicated by having to enter into an adversar-
ial situation with the medical establishment, the pain can
only be intensified. Surrogates should not have to bear the
burden of proving that their loved one meets a specified "ob-
1 ThePresidents Commission for the Study of Ethical Problems in Medicine;

the Hastings Center; the American Academy of Neurology; the American
Medical Association through its Council on Scientific Affairs and its Council
on Ethical and Judicial Affairs; and the United Kingdom Institute of Medical
Ethics, to name but a few.
131
jective" criterion for death. Increasingly, families and legally

recognized surrogates can simply decide for themselves what
should be done, with the knowledge that their right to make
a moral, philosophical, or religious determination of when
death has occurred will be recognized by the civil authorities.
This approach will not solve all our problems, however,
and may even create a few new ones. What would happen if
a shooting victim were to enter a persistent vegetative state
and after a few weeks or months, when the possibility of a
recovery was deemed hopeless, the family decided to with-
hold food and water—the usual method for bringing such
cases to closure. Who would bear the responsibility for the
resulting death—the attacker or the family? This defense has
actually been tried in a criminal case, and was rebuffed, but
we may not have heard the last of it. And who bears the fi-
nancial responsibility for those choosing a whole-brain def-
inition of death requiring expensive long-term maintenance?
Insurance companies may simply write such "catastrophic
health care" out of their policies; many already have. In the
case of individuals with families, the family would presum-
ably have to pick up the cost. But what about the occasion-
al patient with an advance directive specifying strict adher-
ence to whole-brain death and treatment at all costs, but
without a family or insurance? Or the patient without a di-
rective and without a surrogate, especially if he or she is men-
tally incompetent? Should the state pay the costs in these
cases, for example through Medicare? Can the state be the
surrogate, or appoint a surrogate?
132
It is conceivable that in certain limited and clearly de-

lineated instances it may be useful to have a definition of
death based not on specific anatomical considerations but,
as Veatch has suggested, on the irreversible loss of con-
sciousness. Such an understanding of death might also alle-
viate one of the more troubling aspects of ending care for pa-
tients in a persistent vegetative state. Societal sanctions and
legal protections aside, withholding food and water can seem
uncomfortably close to active killing, for both medical staff
and patient families. To fail to resuscitate, or even to fail to
supply crucial medicine, can be rationalized as "letting na-
ture take its course"; both simply involve a failure to take ac-
tion. Withholding food and water involves the purposeful
initiation of a process that will inevitably and shortly lead to
total somatic-cell death. Some, health-care professionals in-
cluded, agonize over whether this is not a form of homicide,
or at best, active euthanasia. But when the decision was made
and accepted that patients with no brainstem function are
dead, there was also an initial unease among many caregivers
about removing such patients from life-support systems. But
now, although this is still never done casually or unfeelingly,
it has become accepted as a normal and necessary part of
medical practice. If we as a society could agree that patients
after some specified length of time in PVS are also clinically
dead, it is possible that this final act, while still incredibly
painful, might be made less traumatic for all concerned.
As resuscitative procedures continue to improve, along
with the ability to maintain persons in a persistent vegetative
133
state for long periods of time, the associated problems can

only become larger and more pressing. Both Medicare and
private insurance companies represent a pooling of resources
by collectives of people seeking to underwrite the costs of
their medical care. If maintenance in a persistent vegetative
state cannot possibly result in restoration of life, yet draws
large amounts of money from the common pool over indef-
inite periods of time, then decisions to maintain people in
PVS should have the full and informed consent of all mem-
bers of the pool — of society. It may thus be time to move
this debate out of the academic journals and professional
meetings into the larger arena of political discussion. And we
should all join in that discussion.
134
6
Standing at the Abyss:

ViruseSy Spores, and the
Meaning of Life
Not people die but worlds die in them.

—Yevgeny Yevtushenko
Even under the most sophisticated microscope,

there is very little difference in the appearance of a cell at the
moment of its death and one that is perfectly healthy, just as
there is little in appearance to distinguish someone who has
just died from someone who just fell asleep. Within a few
moments a dead cell may burst open or fragment into apop-
totic bodies, but if the cell is kept at room temperature it
may not manifest these hallmarks of death for several hours.
135
So how do we know when a cell is dead? This is an impor-

tant question, because the death of a living organism begins,
as we have seen, with the death of a portion of its cells. If we
are to understand fully the meaning of death, we need to un-
derstand what it is that is switched off inside an individual
cell when it dies—what it is that returns it to chaos and to
silence.
When biologists look at cells under a microscope, there
are several practical means they can use to decide if a partic-
ular cell is dead or alive—the cellular equivalents of taking
a pulse or checking for signs of breathing. However, these
means are inexact. For example, a dye like Trypan Blue is ex-
cluded from live cells, and taken up by dead cells, making
them appear bright blue. But what such dyes really measure
is the ability of the cells plasma membrane to exclude or take
up the dye. Practice has shown that this correlates reasonably
well with the cell's being alive or dead, but it is nothing more
than a reasonable correlation. There is no way to be ab-
solutely sure of the vital state of a cell by looking at it, unless
it is so dead it has begun to fall apart. So what exactly is it
that is missing in a cell when it dies? What qualities define a
cell as being alive, the absence of which would make it dead?
There are many criteria used to define life in a cell.
Perhaps the most important one is the ability to consume en-
ergy-rich materials (nutrients), extract the energy from them,
and then use that energy to carry out the various chemical
reactions supporting life within the cell. All living things do
this; it is a process known as metabolism. Cells use energy de-
136
STANDING AT THE ABYSS
rived in this fashion — metabolic energy—to form their

structural and functional components, to reproduce them-
selves, either sexually or by simple fission, and to respond to
the environment, for example to move about in search of
food, or to escape from toxins or predators. All single-cell or-
ganisms, and multicellular organisms that do not generate
their own heat, are also dependent on ambient thermal en-
ergy from the sun. The biochemical reactions necessary to
extract energy from food simply do not work well as tem-
peratures drop toward the freezing point of water, because
these reactions are almost always dependent for their chem-
ical integrity on water in the liquid rather than the solid
state. "Warm-blooded" animals use metabolic energy to-
gether with ambient solar energy to keep their internal tem-
peratures within a reasonable working range.
For most biologists, then, the various definitions of life
can nearly all be traced back to the presence within the cell
of an active metabolism — an ability to extract energy from
food and use it to carry out the range of biological functions
that we call life. But the definition of life (and indirectly the
definition of death) becomes more complicated when we
consider a survival mechanism called cryptobiosis, in which
the organism using it, by virtually any criterion we could
apply—including intracellular metabolism — would in
many cases be dead. The dilemma this peculiar state poses is
that it is reversible. At the end of the cryptobiotic state the
organism reemerges, completely restored to life — able to
feed, to move about, and to reproduce its own kind. This
137
phenomenon was studied intensely in Europe in the nine-

teenth century, first of all because many people found it hard
to believe, but secondly because it stirred popular as well
as professional speculation about the possibilities and very
nature of resurrection as described in the Bible. These kinds
of discussions may seem sophomoric today, but issues like
spontaneous generation and evolution, along with the revival
of spores, posed major challenges to much of the inherited
wisdom of the nineteenth century.
Cryptobiosis is one of a number of strategies cells devel-
oped to deal with an emerging crisis a billion or so years after
life first appeared. As cells happily followed the dictum to be
fruitful and multiply, the inevitable happened: they did, and
life on earth began to get pretty crowded. Living organisms
had to resort to increasingly clever tactics to stay on top in
the fight for ever-diminishing resources. Cells began to push
into rather unlikely biological niches to escape from the in-
tense competition. There are certain environments on earth
that can support life for most of a yearly cycle, except for pe-
riods of extreme temperature, or lack of water or nutrients,
or perhaps extreme salinity. In order to exploit these niches
during the seasons when conditions for life were favorable,
some organisms learned to fake death during the off-season;
they became cryptobiotic.
This reversible deathlike state was known already to
moneran bacteria, quite likely before eukaryotic life forms
ever appeared, and a number of them still practice it today.
138
It is one of the few ways they have to escape the only kind of
death they know — accidental death. Bacteria in this state
are known as spores. Cryptobiosis is also used by many pro-
tists, which in their cryptobiotic form are generally referred
to as cysts. And it is even used by a few multicellular animals,
as we shall see.
In bacteria, the process of spore formation, or sporula-
tion, has been studied most intensively in the genus Bacillus.
The most common signal inducing sporulation in these bac-
teria is depletion of nutrients from the environment. Rather
than simply starving to death, these cells have devised a
means of hanging around until things get better. The fall in
levels of intracellular ATP (and the related molecule GTP) re-
sulting from starvation causes the cells first of all to stop di-
viding and to enter into a stationary phase. This is followed
shortly by the expression of a specific genetic program con-
cerned with sporulation. The genes in this pathway guide the
cell through a series of events that starts out somewhat like
another round of cell division. But in this case the two
daughter cells are not equal, and they do not pull apart. One
daughter begins the transition into a spore; the other daugh-
ter wraps itself around the spore-daughter and helps it in its
transition. One of the first things that must be done is to
surround the developing spore with a thick protective coat
that will prevent damage by chemicals. Unlike a fully viable
bacterium, the spore will be unable to repair damage to it-
self. This introduces a serious problem: externally induced
139
damage may accumulate beyond the point where the spore

can function once it is revived. It is therefore essential that
potentially harmful substances be kept out.
Both daughters contribute energy and materials to pro-
duction of the spore coat. Once the coat is finished, water is
drained from the spore and its important role in stabilizing
internal cell structures is often replaced with a simple sugar
called trehalose. As water disappears, the shrinking cell is
pumped full of calcium and stimulated to produce a com-
pound called dipicolinic acid (DPA). These two molecules
complex with protein structures in the sporulating cell to
make it rigid, and at the same time highly resistant to heat
and radiation damage. When all this is finished, the nurtur-
ing daughter dies, disintegrating and releasing the mature
spore-daughter into the surrounding environment.
What is released is a dry, hollowed-out shell of the orig-
inal cell. It is like a city with no people in it. The basic struc-
ture of the cell is preserved exactly as it was before. The all-
important DNA is intact, although coiled tightly into a dense
strand that cannot be read. Cellular organelles such as ribo-
somes are preserved for the anticipated return to a living
state; modest stores of food may be set aside to help get
things restarted. But the spore is without internal motion
or metabolic activity. It does not have enough water to sup-
port metabolic processes. It does not take in nutrients, nor
does it extract energy from the environment or from stored
nutrients. It does not need energy; all its energy-consuming
activities are shut down. That there is no requirement for
14O
metabolism in cryptobiosis is demonstrated by the fact that

spores dried even further and frozen to temperatures near
absolute zero, where no metabolic processes known to sci-
ence could possibly take place, can recover perfectly well
when returned to room temperature. We will return to this
point shortly.
A spore can remain in the cryptobiotic state for many
years; survival for periods of fifty or 100 years or longer, al-
though unusual, has been convincingly demonstrated.
Spores are resistant to conditions that would be lethal for a
living cell — extremes of temperature or drought, intense ra-
diation, or lack of food and water. In fact, they are among
the most resistant biological structures on the face of the
earth. Spores also serve to distribute the bacteria they repre-
sent over a wider area, where conditions may be more sup-
portive of life. Almost weightless, spores can be picked up
and transported long distances on even gentle breezes.
Because of their unusual stability, bacterial spores pre-
sent an interesting environmental challenge to humans.
Disease-causing bacteria in their cellular form are readily
killed by simple treatments such as exposure to soap or
other mild chemicals, or heating to modest temperatures.
But spores from these same bacteria are unfazed by such
procedures; the only safe and practical way to kill them is
by steam at high pressure. This is the principle behind a
scientific instrument called the autoclave, and its home
equivalent, the pressure cooker.
Although for all practical purposes dead, a spore clearly
141
remains sensitive to its environment. It can tell when condi-

tions to support life have returned to normal. Usually this
means the reappearance of food. When food substances
come in contact with the spore's outer coat, they trigger a se-
ries of reactions that completely reverse the process of spore
formation and restore the spore to a full and normal life as a
bacterium. The coat breaks down; the calcium and DPA are
flushed out of the cell and replaced with water. The trehalose
often acts as a nutrient to get the cell up and running.
Eventually external nutrients rush in and are promptly me-
tabolized into usable energy. After a round or two of cell di-
vision, a revived bacterium is impossible to distinguish from
a bacterium that has never sporulated.
Apparently, then, a spore is not dead—but why not? If
it shows absolutely no evidence of life, can it truly be con-
sidered a living thing? What property does it retain that
allows us to define it as alive? Reversibility of the deathlike
state is an intuitively attractive way out of the dilemma, but
what exactly does that mean? We know that gradually, over
time, spores fail to respond to conditions favorable to growth
by reviving. Did such spores "die" during the spore period?
If so, what was different about them before and after they
died? What thin line did they cross? If we cannot answer
such questions, we really cannot understand what death
is. These questions are as difficult for biologists as they are
for philosophers. But if we follow the trail of cryptobiosis a
bit further, we may begin to get a hint of where the answer
may lie.
142
Protists continued the tradition of cryptobiosis, refining

it and improving on it. Protists are even more fragile than
bacteria, and more sensitive to changes in the environment.
Like bacteria, they enter into a cryptobiotic state in response
to adverse conditions — overcrowding and a build-up of ex-
cretory products, lack of food or water, too little oxygen, too
much or too little salt. One of the first things most protists
do as they begin the process of encystment is to curl up into
a sphere, to minimize their surface-volume ratio. Then they
begin a process that will strip them of any unnecessary bag-
gage as they head into a state that will mimic death. Final sets
of instructions are read from the DNA; some of these in-
structions direct the encystment process; other messages will
be stored for use when and if the encysted cell returns to ac-
tive life. Then the DNA is shut down and wrapped tightly in
histone proteins. If the cell has macronuclei, these are fused,
and many of the excess DNA copies are destroyed.
Any remaining food in the cell, along with cell parts not
absolutely needed for survival, is burned for energy to fuel
the encystment process. Extra mitochondria are set up to
help churn out the enormous amount of ATP that will be
needed over the next few hours. Most of this energy is used
to manufacture a tough outer coat that serves the same pro-
tective function as the coat around a bacterial spore. The
final rounds of protein synthesis are pushed through the
ribosomes, and then the ribosomes are shut down. Some of
them are burned together with excess mitochondria to pro-
vide a last bolus of energy to complete the encystment
143
process. As the coat is being assembled, water begins to be

pumped out of the cell, reducing the overall cell volume by
as much as ninety percent. In many cases the lost water is
again replaced by trehalose, which again helps keep cell
structures from losing their shape during the cryptobiotic
period, and provides a modest store of food for the recovery
period.
The resulting cysts, like bacterial spores, are incredibly
durable. In most cases they exhibit absolutely no metabolic
processes, mostly because of the almost total lack of free
water. They can withstand temperatures ranging from near
absolute zero to well over 100 degrees centigrade. They can
survive for periods ranging from weeks to decades. Like
spores, they too can sense when external conditions have re-
turned to normal, and then the process of excystment revers-
es the cryptobiotic state in a matter of hours.
Cryptobiosis is not used much in multicellular animals.
A few vertebrates have developed hybernation strategies to
reduce energy demands during periods of cold or depriva-
tion of food or water, but these states never come even close
to the deathlike state of cryptobiosis. There is, however, one
important exception: the embryos of the brine shrimp
Anemia salina. These are not simple single-cell organisms;
by moneran and even protist standards, they are giants.
These tiny crustaceans belong to the same taxonomic group
as the shrimp we use to make jambalaya. They are grown and
harvested commercially for use as food on fish farms. As
their name implies, brine shrimp live in waters with unusu-
144
ally high salt content. They are found in evaporating saltwa-

ter ponds around oceans or seas, where the salt concentra-
tion may be two to eight times that of ordinary sea water.
Brine shrimp produce normal eggs and embryos that pro-
ceed to develop in an ordinary fashion into adult organisms.
But they also produce, particularly as the dry season ap-
proaches, embryos whose development is arrested at an early
(but definitely multicellular) stage, and that are encysted
within chitinous shells similar to those encasing insects like
beetles. These embryonic cysts can survive even if the salt
pond evaporates to complete dryness. The cysts are almost
completely without water; they are tough, dry, minute par-
ticles that might be mistaken for sand. They can exist in this
state, showing absolutely no measurable indication of life,
for many years, which is what makes them valuable as fish
food. Each dried cyst contains enough stored yolklike nutri-
ents to supply food to the embryo upon excystment, which
occurs simply by exposing the dried embryonic cysts to
water. Once excysted, unless eaten by hungry fish fry, the
embryos continue on their journey to becoming full-grown
brine shrimp, as if nothing at all had happened along the way.
Artemia embryo cysts would hardly be worth mention-
ing, scarcely more than an evolutionary curiosity, if it weren't
for a simple yet profound experiment that tells us a great deal
about the definition of life and death at the cellular level. In
this experiment, carried out at Yale University in the early
1960s by Art Skoultchi and Harold Morowitz, a batch of
desiccated Artemia cysts was divided in half. One half was
145
kept at room temperature; the other half was frozen in liq-

uid helium at reduced pressure to an extremely low temper-
ature— less than 2.2 degrees above absolute zero (i.e., less
than 2.2 degrees Kelvin) — and held there for six days.
Absolute zero is -460 on the Fahrenheit scale. It is the point
at which all known physical processes come to a halt. Not
only can there be no biological activity at 2° K; the very mo-
tion of atoms themselves is brought close to a standstill, and
there is no energy or momentum in the system. At -460° F,
the inside of a dehydrated cyst is like outer space: frozen,
inanimate matter surrounded by essentially zero energy. The
implications of bringing a biological organism to this tem-
perature were summarized by the authors:
At these temperatures the only feature of the organism that per-
sists is its structure. While each atom retains its position, its
momentum goes to zero. . . . Warming the system is a random
process, so that the momentum distribution after exposure to
temperatures near absolute zero is independent of the momen-
tum distribution before freezing. . . . If an organism survives
this process, all the information required for a viable system ca-
pable of responding in the appropriate biological way must be
stored in its structure.
When the frozen cysts were brought back to room tem-

perature and placed in dilute salt water, the percentage of
cysts that hatched successfully was not statistically different
from that found in the cysts that had been kept at room tem-
perature. The authors concluded the following from their ex-
periment:
146
S T A N D I N G AT THE ABYSS
The survival of a complex biological system such as Artemia

cysts after treatment at temperatures near absolute zero [argues]
that all the information necessary for the specification of a liv-
ing system is stored in the three-dimensional configuration of
its atoms.
In other words, at -460° F, it is impossible for any dynamic

"vital principle" to exist in accordance with any known prin-
ciples of physics. All that is left is a particular arrangement
of molecules and atoms in three-dimensional space. At ex-
tremely low temperatures, life, by any biological criterion we
might choose to define it, is missing in these cells. By restor-
ing ambient thermal energy and replacing the water neces-
sary to support chemical reactions inside these cells, we can
restore what is, by any biological criterion we might choose,
life. A very powerful argument can then be made that at the
level of individual cells, the possibility of life can be defined as
the interaction of universally distributed thermodynamic ener-
gy with specified biological macromolecules arranged in speci-
fied structures. We must say "the possibility of life," because
this interaction alone will not generate life as we understand
it; it simply creates molecular motions within the structure
that allow cells to convert food and oxygen into biologically
usable forms of energy, which in turn enable the cells to carry
out their ultimate mission — to sustain and protect DNA,
and to enhance the ability of DNA to reproduce itself. But if
the external conditions are right—if the food and oxygen are
there—then life will proceed.
Buried in this definition of life is the clear implication
147
that if we could reproduce these exact structures artificially

and allow them to interact with ambient thermal energy and
supply them with food, we would be able to produce a liv-
ing cell — to produce life. There is absolutely no reason,
based on our present understanding of biology and physics,
to think that this would not happen. The structure of each
of the molecules in a cell, as well as its three-dimensional re-
lationship to other molecules, is ultimately determined by
the cell's DNA. Reproducing these structures and interrela-
tionships would certainly be very difficult, and beyond pre-
sent technology, but theoretically not impossible. This is an
unsettling thought in many ways. We generally consider life
to be fundamentally undefinable, an unbridgeable abyss we
cannot cross. We approach this abyss with understandable
trepidation.
Although this definition of life at the level of individual
cells is extremely persuasive, it is one that very few biologists
are actually conversant with. Most biologists tend to think
of life at the level of whole multicellular organisms, where
the activities of millions if not billions of cells are coordinat-
ed by a central nervous system — in higher animals, a brain.
Death is normally defined by the loss of this coordination,
which then leads to collapse of the entire system and cata-
strophic death of all cells. But in fact, even in multicellular
organisms death always begins with the death of single cells.
If life is the interaction of structure with energy, then it
follows that death at the level of a single cell must represent
the loss of either structure or energy. In the case of Anemia
148
cysts, if thermal energy were never returned to them, they

could never return to a living state no matter how perfectly
preserved their structure might be. On the other hand, we
know that in spite of their tough coating they will gradually
be degraded by toxic oxygen or other environmental chem-
icals, or by incident radiation coming through the atmos-
phere. Because they are metabolically inert, they cannot
repair this damage, which may accumulate until their struc-
ture is altered to a point where application of thermal ener-
gy would not restart metabolism — would not restore life.
This is the likely answer to a question posed earlier about
bacterial spores: what thin line has a spore crossed when it
can no longer be revived? Almost certainly, some critical fea-
ture of its structure has degraded over time such that the ap-
plication of energy to that structure no longer initiates those
reactions that we call life. And so it is dead.
We began an earlier chapter with the question Why
deatht But that is an asymmetric question; in order to answer
it, we must ask another— Why life*. While the study of cryp-
tobiotes points up some of the ambiguities about definitions
of life and death, there is another biological entity that brings
us even closer to some of the most fundamental questions
about the nature of life itself and thus, indirectly, about the
nature of death — viruses.
Viruses have none of the characteristics of living cells
to begin with. Not only are they metabolically inert, like
cryptobiotes, but they also lack any of the structural charac-
teristics we would associate with a cellular origin, such as a
149
nucleus, mitochondria, ribosomes, membrane pumps, and

so forth. They have a coat, but there is almost nothing under
it. There is no way that a virus could be considered alive, in
the sense we ordinarily use that word. Yet if we allow that the
single most important task of living things is to pass on their
genes (DNA) to as many offspring as possible, then viruses are
very much a form of life. For the one thing viruses do have
under their coats is genes; they do have DNA (or RNA, which
the virus, once inside a cell, can convert into DNA). In fact,
viruses are nothing more than DNA (or RNA) wrapped in a
few strands of protein. And by the criterion of reproductive
capacity, pound for pound viruses may be the most efficient
biological entities around. The fact that they must infect a
living cell to reproduce should not be held against them. In
getting someone else to do most of the work for them, they
might well be viewed as among the most successful of all life
forms.
However we view them, viruses do strip the definition
of life to its barest essentials. For example, viruses raise some
intriguing questions about the very act of reproduction.
Humans ascribe all sorts of noble reasons to their own re-
productive efforts. Having children is variously held as the
highest expression of the love between a man and a woman,
an expression of confidence in the future of the race, and the
central experience of human life. Rarely if ever would we de-
scribe our reproductive activities in terms of some common
biological imperative to pass on DNA.
Higher-order reasons for generating offspring might
ISO
even be extended to creatures other than ourselves. We can

imagine an element of rational reproductive will among
many of the animals in our environment — horses, say, or
eagles, or cats and dogs. We readily recognize their courting
and mating practices; we admire their devotion to their
young. But if we were to let our minds wander to the repro-
ductive activities of lower animals like starfish or molluscs or
worms, ideas about reproductive will are apt to be replaced
by images of blind, mindless mating impulses. By the time
we got to something like bacteria in our considerations, we
would probably be at a loss to imagine what could possibly
be driving them to reproduce. Love of their offspring? Belief
in the future of their race? On the other hand, we would at
least view them as living things, subject to whatever repro-
ductive imperatives are involved in the propagation of life.
But what about viruses? What could possibly drive a
strand of DNA wrapped up in a handful of inert proteins to
want or need to reproduce itself? Where does that reproduc-
tive imperative — for surely it is that—come from? What,
if anything, governs it?
These questions bring to mind an entirely hypothetical
but nonetheless very interesting situation I heard described
many years ago. It may ultimately help us to understand, or
at least appreciate, the dilemma posed by viruses. In this sce-
nario, we are asked to imagine the following. A world-
famous university neurosurgeon, renowned for his ability to
remove certain malignant tumors in the deepest recesses of
the brain, one day learns that he himself has exactly such a
151
tumor, in just such a place — the brainstem. At first he pan-

ics, for he knows the tumor is fatal, and he also knows that
no one else in the world can remove the tumor without very
likely killing him. But then, in a brilliant creative flash, he
realizes that under the right conditions—with a bit of prac-
tice and a little help from his friends — he can probably re-
move the tumor on his own. The brain has no pain recep-
tors; if he can get someone to open a portion of his skull
under local anesthetic, then by using appropriate combina-
tions of mirrors and surgical instruments, he should be able
to perform the difficult surgical procedure himself.
After a few weeks of practicing with lights and mirrors,
and running his assistants through endless drills, he is ready
to go. The operation is long and difficult. Opening the skull
was more painful than he thought. As familiar with the op-
eration as he is, in the end he can't quite watch as the whin-
ing saw cuts into his own flesh and bone. He waits impa-
tiently as his assistants lay back the skull flap and gently push
apart the various layers of the brain to expose the tumor—
the "easy stuff" he knows they are qualified to do. Finally,
when all is ready, he picks up the scalpels and various probes
from the tray in front of him. Closing his eyes for a moment,
he mentally runs through the ensuing steps, sensing in his
hands and in his mind's eye the necessary reversal of hand
movements he has practiced for mirror-image surgery. He
opens his eyes, takes a deep breath, and begins. Two hours
later, he indicates by a wave of his scalpel that he has fin-
ished. The concentration required to prise the tumor from
152
surrounding brain tissue without harming the brain itself has

exhausted him completely. When he finally drops the of-
fending tumor into the surgical specimen pan, he almost im-
mediately falls into a deep sleep. His assistants drain and
close the wound, and stitch his skull back together. To the
great relief of everyone involved in this strange enterprise, the
surgeon wakes the next day, and his previous symptoms
rapidly disappear. It is clear the operation was a success.
Such a story, if true, would instantly be converted into
several books, a TV docudrama, and very likely a movie. Our
surgeon would be feted repeatedly by adoring medical
groupies, and invited to speak before the American Medical
Association. The best and the brightest young surgical resi-
dents would compete fiercely to get into his neurosurgery
service at the university. But in focusing on the human and
medical drama of this astounding achievement, we would
miss an opportunity to take a fascinating look into what we
might call the ultimate abyss of biology.
Let us go back over this episode from a purely biological
point of view. In the movie, it will be implied that our sur-
geon-hero brilliantly deduced that he had a life-threatening
tumor in his brain and decided on a bold course of action to
remove it. But in reality, was it not the brain itself that made
the diagnosis and mapped out the course of action? The
brain, using information supplied to it during many years of
medical education and training, was able to interpret cor-
rectly certain data it had acquired about its own condition.
Using the eyes and ears feeding into it, consulting its data
153
banks and employing its own capacity to reason, it deter-

mined that some of its cells had become cancerous. The
brain knew it was going to die. The initial jolt of this recog-
nition — (What else can we say of it? It was a recognition.)
— triggered a release of neuroendocrine hormones that
caused the rest of the doctor to panic.
But then the brain realized that it had all the informa-
tion it needed to rescue itself from extinction; it could, in
fact, repair itself. The doctor it inhabited was equipped with
an excellent set of hands and fingers that the brain could
control with exquisite precision. The brain directed the rest
of the doctor to set up a series of lights and mirrors so that it
could use other input sensors — the eyes — to guide those
hands and fingers through the required sequence of manip-
ulations. It knew that it would have to remake certain of its
connections to get the hands and fingers to perform the
needed manipulations correctly, so it directed the doctor to
practice while it studied the reaction and rewired itself. And
when it was all done, the brain accomplished exactly what it
set out to do — it saved itself from certain death.
In casting about for an explanation of this peculiar yet
highly directed form of behavior, it would not be unreason-
able to ask what made the brain behave in just this fashion,
at just this time. Why did it want to survive* What does it
even mean to say that a brain, in and of itself, could "want"
something? But can we really doubt that all of the percep-
tions and reactions described above were carried out in the
brain, and the brain alone? Could any other part of the body
154
have perceived and reacted in the same way? No. Simply and
finally, no.
So here we have this kilogram or so of pale, mushy tis-
sue directing a remarkable sequence of reactions designed to
save itself. Why? What drove it? In trying to answer this
question, some biologists—cell biologists—would take the
level of analysis down one notch. After all, they would say, a
brain is composed of cells; so in the end it must be individ-
ual cells that have the will to survive. This would not be im-
possible to imagine; single-cell monerans and protists are
equipped with a variety of responses to assure, or at least en-
hance, their own survival. For example, individual cells liv-
ing on their own can detect noxious substances in their en-
vironment and move away from them or retreat into a state
of cryptobiosis. They can produce substances that kill or oth-
erwise neutralize other single cells that can kill or otherwise
neutralize them. These primitive cells (which certainly do
not have brains) show a definite "will" to survive, so why
shouldn't brain cells? If we are, in a sense, the biological heirs
of these cells, perhaps some manifestation of a will to survive
in our own cells is simply part of our evolutionary inheri-
tance.
But other biologists — let us call them molecular biolo-
gists — would want to drop to an even more fundamental
level of analysis. Without doubt, every single action of a cell
is directed by its DNA. Like a hologram, every cell of the body
has embedded in it a DNA image of our complete biological
selves. If every action of a cell is guided by its DNA and
155
nothing else, it is hard to escape the conclusion that it

wasn't really the brain that sensed approaching extinction in
this little fantasy, nor even the brain's cells. It must have been
DNA.
Which brings us back to viruses. Viruses have certainly
been on this planet much longer than human beings. Their
ability to survive and reproduce is abundantly clear. In in-
terpreting our own lives and deaths, humans tend to spin
elaborate stories about love and free will. Here we stand,
complex beings filled with emotions, dealing as best we can
with biological imperatives we don't always understand. We
are nurtured and we grow; we love, marry, and have children,
whom we in turn nurture and raise to become sentient
adults. And there stands the virus, a few proteins wrapped
around a single strand of DNA. This smallest of all biological
entities is endowed with an incredible drive to reproduce it-
self. This minute speck, ten thousand or more times smaller
than a bacterium, straddling the line between the living and
the nonliving, can lay waste to a human being in a matter of
days. In forms like the Ebola or Marburg viruses, or HIV, it
has the potential to wipe out a significant portion of the
human species — simply by following its destiny to repro-
duce itself, over and over and over again. A destiny written
into a simple strand of DNA.
Is this the end of our quest to understand life and death,
this double strand of four nucleic acids combined into a
seemingly endless string of hieroglyphics? Embedded in this
hologram are instructions specifying the composition and,
156
S T A N D I N G AT THE ABYSS
ultimately, the exact placing of every molecule involved in

the pure structure of a cell, the structure that interacts with
ambient energy and food and oxygen to allow the cell to
carry out its mission. And what is that mission? It is nothing
less, and nothing more, than to facilitate copying and trans-
mission of the DNA itself to the next generation. Our own
DNA seems a bit less sure of itself than viral DNA; it makes a
hundred trillion copies of itself—one set for each cell in the
body—to ensure the transmission of just a few copies to the
next generation. And then it directs the destruction of the
other hundred trillion copies. And we die.
What drives DNA to reproduce itself? Why should it
bother? Do the individual nucleic acid letters or symbols that
make it up spell out a message that animates the reproduc-
tive process? Does our own DNA contain this same message?
Scientists in this century have deciphered the genetic code—
the language in which all genes are spelled out in our DNA.
But in fact, the genes that direct the construction and oper-
ation of our bodies have been found to account for only a
few percent of the DNA we carry in our cells. What is written
in the rest of our DNA? When translated using the standard
genetic code, it is gibberish. As mentioned earlier, we now
know that the vast majority of our DNA is never used to code
for the proteins needed to conduct the daily business of the
cell. Yet we have continued to carry this excess DNA — at
great expense in terms of having to synthesize it every time a
.cell divides — over millions of years of evolution. So what is
it doing? When scientists look at DNA with algorithms that
157
are used to analyze the structure and information content of

all human languages, it is here—in the so-called nonsense
DNA, rather than in the regions coding for protein—that the
greatest similarity to human language is found. Is this where
the message that tells DNA it must reproduce itself is buried?
Could this be where concepts like language and poetry and
life after death, concepts that we think arise in our minds,
are ultimately written? We do not know. This is where biol-
ogy tapers off into pure chemistry and the thread of our ex-
istence disappears. This is the edge of the biological abyss,
ill-defined though it may be, where the energy that perme-
ates the universe interacts with structure to produce life. It is
at this interface that we see both sides of ourselves, and where
human beings sometimes see the face of God.
158
7
Coming to Closure
Listen carefully; be attentive and alert. Death has come to

you. It is time for you to depart this world. While you must
face this reality alone, know that you are not the only one, for
death comes to all. Do not cling to life because of sentiment,
and do not fear to go on. You do not have the power to stay,
—The Tibetan Book of the Dead
And so we turn once again to our patient, the man

whose myocardial cell we watched die at the very beginning
of this story, and whose heart nearly stopped beating as a re-
sult. That he did not die within minutes of the onset of his
heart attack is a tribute to his wife's prompt intervention, her
knowledge of CPR, and the swift and effective follow-up by
the first-response and advanced life-support teams. But what
159
is his status now? Have these interventions prolonged his life,

or have they simply prolonged his death?
A little more than six weeks has passed since he was
brought to the hospital. He still lies quietly in the intensive
care unit: still breathing unassisted, still warm to the touch.
Occasionally he moves his head or extends a finger. He
emerged from deep coma and opened his eyes after the
fourth day; these eyes now blink occasionally and move, but
they do not see. They do not track the nurses and technicians
who constantly move about him, monitoring his vital signs.
They do not see the soft colors of the room, or the gleaming
surfaces of the instruments efficiently arrayed around him.
They do not see his wife or his two children or his friends
who bend anxiously over him, hoping for some sign of
recognition, some indication that he realizes they are there.
But he cannot signal to them what he does not know. He is
no longer able to know anything; it is clear that he has no
cognitive function left within his brain.
Since he opened his eyes nearly six weeks ago, he has
been on something approximating a sleep-wake cycle, indi-
cating that the ascending reticular network in his brainstem
is functioning. At night his eyes close and he seems almost
comatose again, but during the day they open and resume
their random movements. Although he seems to swallow his
own saliva occasionally, he cannot chew or swallow food in
an organized way, or drink and swallow water; he is given
these substances through gastric feeding tubes or intra-
venously, as necessary. He is completely incontinent and is
16O
COMING TO CLOSURE
diapered. He recoils from loud noises, and gags or coughs

when something is put in his throat. He is bathed and ex-
amined regularly, and is put through a daily regimen of as-
sisted limb movements to prevent muscle atrophy. He has
been placed on a special mattress to prevent the development
of bed sores.
How did a vital, sentient, feeling human being—a man
who laughed, played with his children, skied, and read
books—come to be what we see before us now? He has come
to this state because the brain, for all its power to create, to
organize, to direct, is an exceedingly fragile and delicate
organ. Above all other organs in the body, it is dependent on
an uninterrupted flow of blood to deliver precious food and
oxygen. The heart, of course, is also heavily dependent on
the same constant supply of blood. His recent heart attack
happened because of a gradual cut-off of blood to a localized
region of heart muscle. This myocardial ischemia and re-
sulting infarction involved only a small section of cardiac
muscle, but one large enough that its loss, along with the
muscle lost in his earlier heart attack, caused the entire heart
to stop pumping for a brief period. Had the comparable
event occurred in his brain — a loss of blood to a restricted
region through blockage or bursting of a local blood vessel—
the result would have been a stroke. But with his most recent
heart attack, a combination of interrupted blood flow, and
more importantly the loss of blood oxygen through inter-
ruption of his breathing, resulted in a temporary state of
total brain ischemia.
161
Of course, all the other cells and tissues in his body also
experienced the same transient total ischemia when his heart
stopped beating, and his breathing faltered, but the impact
of ischemia on the brain is different. Although brain cells
may seem to do very little real work—they do not contract
to lift things or to pump blood, nor do they manufacture
huge amounts of proteins for export — they nevertheless
consume oxygen, and fuel in the form of glucose, at a rate far
in excess of any other cells in the body. The major use for this
oxygen and fuel is to generate energy to drive the large num-
bers of membrane pumps found in all brain cells. As in any
other cell, these pumps are absolutely essential to keep water
out and to maintain ionic gradients across the cell mem-
brane. At rest, brain cells actively pump out sodium and cal-
cium, as well as water, and must prevent these molecules
from reentering. The brain also uses pumps selectively to
build up large internal stores of potassium, which it must
prevent from spontaneously leaking out.
The maintenance of these ionic gradients across the
outer cell membrane is what generates an electrical potential
in the nerve cells (neurons) of the brain, and allows them to
pass a message along to the next cell. In response to either in-
ternal or external stimuli, a given neuron can depolarize, let-
ting the ions briefly rush toward equilibrium across the
membrane, collapsing the ionic gradients and sending an
electrical current racing along the cell's surface. Some neu-
rons send out very long fibers called axons, which may con-
nect either with other nerve cells, or with a target organ such
162
COMING TO CLOSURE
as muscle. If the neuron is connected to another neuron

through that cell's receiving fiber, or dendrite, the electrical
current jumps the gap (synapse) between them and depolar-
izes that nerve cell as well. But almost before this impulse has
reached the next cell, the ion pumps located all along the
neuronal membrane are already at work pushing sodium
ions out and potassium ions back in. This process continues
from nerve cell to nerve cell until the electrical signal reach-
es its target. Because nerve cells do this over and over, and
must collapse and restore the ionic gradients extremely
rapidly, they have many more membrane pumps than most
cells. And these pumps use enormous amounts of cellular en-
ergy, or ATP.
In other cells in the body, a large portion of the glucose
and other nutrients brought in with blood is usually stored
in the form of glycogen or fat to serve as reserves for future
energy demands. When excessive demands arise, the reserves
are burned together with oxygen to produce ATP, the form of
energy used to drive all cell processes. It is even possible to
generate a modest amount of ATP from these reserves in the
absence of oxygen, in a process called anaerobic metabolism.
If oxygen deprivation does not go on too long, anaerobic
metabolism may be sufficient to meet an ordinary body cell's
needs for some time.
Again the brain is different. It burns up nearly all the fuel
coming into its cells almost the moment it arrives, convert-
ing it to ATP and another chemical form of usable energy
called creatine phosphate (CP). This requires a constant, un-
163
interrupted flow of oxygen. Few if any of the nutrients are

stored for future use. The ATP and CP in turn are consumed
almost immediately to fuel each cell's enormous number of
membrane pumps. Thus brain cells are always living on the
edge. They never relax, never store up energy reserves that
might see them through anything but the briefest period of
deprivation. And at least for human cells there is no possi-
bility of entering a quiescent state like cryptobiosis until the
danger is past.
The physicians overseeing our patient's case are more
than aware of the fragility of the human brain. They know
that very large numbers of his brain cells have been irre-
versibly damaged. They are now certain that he has entered
a persistent vegetative state from which he will not recover.
Tests with a new technology called positron-emission to-
mography ("PET scan") have shown that the rate of glucose
metabolism in his cortex is less than thirty percent of nor-
mal. Electroencephalographic readings also suggest greatly
reduced cortical function. Radioactive tracers injected into
the bloodstream indicate that blood flow to the brain is less
than a third the normal rate. All these measurements have
been repeated several times during the past few weeks, each
time with the same result. It appears that the majority of cells
in his cortex have simply died. The doctors know that such
patients at autopsy often show massive shrinkage of the cere-
bral hemispheres, which pull back from the skull case and
collapse onto the brainstem. His brainstem itself seems to be
164
COMING TO CLOSURE
in reasonably good shape, though; it is directing all the ac-

tions his body is still engaged in.
All of this has been explained sensitively and compas-
sionately to his wife. She has also been told there is no
treatment possible; damage from loss of nerve cells is not
reversible. The likelihood that he will ever recover con-
sciousness is now judged essentially nil, and even if he did,
the combined damage to his heart and brain would preclude
anything remotely resembling a normal life.
His wife had prepared herself mentally for this outcome,
which became increasingly likely when he did not regain
consciousness within the first week after his heart attack. She
also understands that he cannot be declared legally dead. The
body she visits every day still retains the vast majority of its
somatic functions, and while it is painfully familiar to her in
its physical appearance, the man she knew as her husband is
irretrievably lost. It is a situation they had both foreseen and
had discussed in detail. As in so many other things in their
life together, they were of a single mind about what to do in
such a case. With help from an attorney, they both drew up
simple living wills. The state in which they reside allows
them to stipulate through such advance directives that
should either of them enter a persistent vegetative state, with
no hope of recovery, they would wish no life-prolonging pro-
cedures to be administered, including artificial delivery of
food and water. Each promised the other that they would do
everything in their power to ensure that these wishes were
165
carried out; the durable powers of attorney they granted one

another gave each the legal authority to keep the promise.
Each asked only that all necessary steps be taken to prevent
any pain or discomfort.
Last night the patient's wife met with her two children
and their spouses, and told them she wanted to request that
all further treatment be suspended, specifically, that food and
water be withheld. They all agreed, sadly, that this seemed
the best course of action. This morning she returned to the
hospital and asked that the document indicating her hus-
band's wishes, already on file with his hospital records, be
put into effect.
Later this afternoon, her husband will be disconnected
from the various monitors and warning devices that have
kept watch over him since his arrival in the icu. The i.v.
drips and feeding tubes delivering food, water, and medicine
to his system will be removed, and he will be transferred to
a simple but comfortable room on the fourth floor. Were he
suffering from total brain failure—had his brainstem been
damaged to the extent that he could not breathe without
a respirator—disconnection from his life-support systems
would bring death in a matter of minutes. The exact course
of events in this case is hard to predict. Death will come from
starvation and dehydration, perhaps in a few days, possibly
in a week or more. But it will come soon. The nursing staff
will not abandon him. They will bathe him, and keep his
mouth and eyes moist. They will not exercise him, but they
166
COMING TO CLOSURE
will move him around on the bed. This is done more to re-
assure the family than to help the patient, for he is long past
the possibility of any personal awareness of pain or discom-
fort. But it is also, the staff would tell you, for the dignity
due the memory of any human being.
Most likely he will die because dehydration will induce
an electrolyte imbalance in his blood, which will cause his
heart to stop beating once again, interrupting the flow of
blood to his brain. Then his body will experience the total
brain ischemia that weeks ago deprived him of his cortical
function — his humanness—but this time it will take him
through to the end. There will be no attempt to stop the
process; his chart will be clearly marked DNR—Do Not
Resuscitate. Once his heart stops, the consequences will be
rapid and irreversible. Sensing the sudden absence of oxygen
and glucose, the brain will at first increase the diameter of its
internal blood vessels in an attempt to bring in more blood.
But the resulting increase in fluid leakage from these vessels
will cause edema, swelling of the brain that will actually
crush the vessels and cut off any remaining blood flow.
A sequence of events similar to what we saw earlier in the
necrotic death of his heart cells will take place, but in a much
compressed time scale. Any scant reserves of fuel will imme-
diately be converted through anaerobic metabolism into ATP,
which in turn will immediately be grabbed by the membrane
pumps in one last, vain attempt to maintain the cell's os-
motic and electrochemical balance. The ATP and CP within
167
the neurons will drop to dangerous levels within seconds,

essentially disappearing within two to three minutes. A few
minutes after that, the membrane pumps will shut down
permanently for lack of fuel, and allow water and calcium
ions to flow unimpeded into the cells. The water will cause
the cells to swell and strain against one another; the calcium
will begin to corrode the mitochondria, which will sit idle
for a few minutes and then puff up and start to unravel. In
the nucleus, the increased sodium and calcium levels will
cause the chromosomes to clump into useless, gummy
strands of DNA and protein. The ribosomes, running full
blast just moments before to churn out proteins needed for
the patient's brain cell function, will fall apart and drift off
into the cytoplasm.
Slowly at first, but with gathering speed, the individual
brain cells will detach from one another, rounding up and
pulling back the axons and dendrites that had sought each
other out during his lifetime of thinking and remembering.
Although the cells will not burst open in quite as violent a
way as his heart cells did earlier, their membranes will devel-
op massive leaks, and they will spill their contents into the
fluid that bathes the brain and extends down into the spinal
cord. But this time there will be no army of white cells
marching in to remove the dead, or fibroblasts to lay down
scar tissue. The blood in which the white cells travel will no
longer reach the brain, and at any rate the white cells them-
selves will be trying desperately to deal with their own sud-
den lack of oxygen. In a few minutes they too will burst apart
168
COMING TO CLOSURE
under the strain of inrushing water. The patient will of

course be unaware of any of this, or that his body has begun
the process of unraveling itself, preparing for a return to the
elements from which it came — to unconnectedness, to
chaos, and to silence.
169
Epilogue
And every time again and. again

I make my lament against destruction.
—Yevgeny Yevtushenko
Wedie because our cells die. Clearly the definition

of humanness must transcend descriptions that can be de-
rived from studying the lives of individual cells; yet it is true
that when death comes for us it gathers us in cell by cell
by cell. The death of our cells, as we have seen, is not an a
priori requirement of life. It is an evolutionary consequence
of the way we reproduce ourselves, and of our multicellular-
ity. For reasons which are difficult to discern across thou-
171
EPILOGUE
sands of millions of years of evolutionary time, the decision

to use sex as a means of reproduction was followed, in the
evolutionary line leading to human beings, by the generation
of reproductively irrelevant DNA. That irrelevant DNA, segre-
gated off into somatic cells, has become us.
DNA has only one goal: to reproduce itself. It does this in
accordance with the same physical laws — the same princi-
ples of thermodynamics — that govern all the rest of the
universe. Once a reasonable number of our germ cells have
been given a chance to impart their DNA to the next genera-
tion, our somatic cells become so much excess baggage. They
serve no useful function, and they— we— must die, so that
change can be transmitted to the next generation.
Under the guidance of DNA, every somatic cell in the
body will senesce and ultimately die on its own. This has
come to be known as programmed death. If cells escape acci-
dental cell death, they will ultimately be instructed to com-
mit suicide — to execute the sequence of events known as
programmed cell death via apoptosis. Most often this happens
when the DNA of a cell has accumulated unacceptable levels
of DNA damage. But death of the body rarely if ever occurs
because of the cumulative effects of sequential, one-by-one
extinction of somatic cells. Autopsies of very old people (over
eighty years of age) usually reveal signs of half a dozen or
more serious ailments that could have been expected to lead
shortly to death. Sooner or later, as cells gradually die off
through apoptosis and critical organs such as the kidneys or
lungs or liver begin to fail because of cell loss, the heart will
172
EPILOGUE
stop beating. Then the death process takes place in a greatly

accelerated fashion. Deprived of nutrients and oxygen car-
ried by the blood, the remaining cells in the body will die a
violent necrotic death in a matter of minutes. Brain cells will
be the first to go; the rest will soon follow.
Whether cells die by necrosis or apoptosis, the key ele-
ment in their demise is the loss of the carefully integrated cel-
lular structure that allows metabolism to sustain itself. In
necrotic cell death, structure is disrupted mostly by the in-
flux of water, stretching and tearing and pulling the cell
apart. In apoptosis, internal structures (aside from DNA) are
not altered so much as segregated from one another as the
cell disintegrates into apoptotic bodies. The individual or-
ganelles are all there, but they can no longer interact. A col-
lection— even a complete collection — of organelles in sep-
arate apoptotic bodies is no more a cell than a collection of
body organs in separate bags is a human being. The individ-
ual organ structures are still there, and may function for
awhile, but the structure of the organism is lost forever. So it
is with a cell dying by apoptosis, shedding parts of itself like
petals from a flower, or leaves from a tree.
The order in which somatic cells die is of no particular
concern to nature, although recently it has become of in-
creasing concern to us. When the heart stops pumping, the
brain cells die first, as we have seen. Other cells follow, the
timing of their deaths determined by their ability to carry
out anaerobic metabolism with food stores set aside for lean-
er times. No one seems to have kept (or at least published)
173
EPILOGUE
accurate records on the point, but we could very likely re-

cover viable cells such as fibroblasts from a human being for
quite some time after complete loss of brain function and an
official declaration of death. Put into culture, these cells
could proceed to complete their Hayflick limit for many
weeks or months after the body from which they came had
died, until they finally succumbed to their own genetically
encoded deaths by apoptosis. Unless, of course, they some-
how got transformed by a virus, in which case they might
carry their DNA hologram endlessly into the future like some
renegade germ cell, or like the cells taken from Henrietta
Lacks's tumor.
We have learned to intervene in the death process start-
ed by the loss of heart cells, and in some cases this interven-
tion works very well. The formerly rapid and irreversible
slide toward death can often be halted. A defective heart can
even be replaced, either by a transplant, or possibly one day,
by a completely artificial heart; the heart, in the end, is sim-
ply a pump. Certain types of damage to the brain can be re-
paired, too, but once neurons die they cannot be brought
back to life, and they cannot be replaced. The technology of
resuscitation has forced us to face squarely the issue of death
as it relates to brain function; we are moving ever closer to
the notion that the death of too many cells in the cortex of
the brain signals the death of the person, if not of the body.
Yet even this redefinition may not be sufficient to address
the problems we have created for ourselves. As Peter Singer,
the eminent Australian bioethicist, has stated in his book
174
EPILOGUE
Rethinking Life and Death: "The patching [up] could go on

and on, but it is hard to see a long and beneficial future for
an ethic as paradoxical, incoherent and dependent on pre-
tense as our conventional ethic of life and death has become.
New medical techniques, decisions in landmark legal cases,
and shifts of public opinion are constantly threatening to
bring the whole edifice crashing down."
Nevertheless, for the present, human beings seem to
have decided that cells of the brain are more important in
defining life than other cells. Nature, of course, would make
no such distinction; from her point of view, a brain is no
more or less important than a lung or a kidney or a foot.
Nature recognizes no hierarchy among somatic cells. Why
do we make such a distinction if nature does not? The brain
evolved to coordinate the activities of the body more effec-
tively, to make the organism it directs better at competing
for resources, for survival, and for the right to pass on a par-
ticular set of genes — a particular pattern of DNA. But some-
where along the way the human brain took a completely
unprecedented turn; it acquired mind. This meant nothing
at all to nature, except as it might promote the welfare of
DNA, but it took us, as biological organisms, into distinctly
nonbiological arenas apparently having little to do with sur-
vival and reproduction: poetry, for example, or pure reason
or pure mathematics; art, religion and music; sitcoms and
soap operas. The pressures that govern our own further evo-
lution are no longer strictly biological; through mind we
have acquired culture, and that, rather than a competition for
175
EPILOGUE
resources needed to survive until breeding age, is now the

dominant selective force in our reproductive success. As
Richard Dawkins has pointed out, although culture exists
only in our minds, it nevertheless has its own evolutionary
momentum, just as genes and DNA do.
We have yet to see how or to what extent or even
whether the acquisition of mind may have changed or may
yet change the natural order of things. Human beings have
escaped the harsh realities of natural selection, but the rest of
the biological planet has not. It is not simply that we have
created mental pastimes which make our passage through life
more pleasant, or at least more tolerable; through mind, we
have begun to alter nature, and even our biological selves, in
ways never before seen in the biosphere in which we evolved.
No longer subject to the early and harsh death nature re-
serves for the weak or the unfit, we have begun to accumu-
late genetic defects that would long ago have been culled by
nature. Medicine in the twentieth century has already en-
abled us to alter the composition of the human gene pool by
keeping alive through reproductive age people who, in a
more natural environment, would have died of genetic dis-
ease. Medicine in the twenty-first century, through gene
therapy, will extend this trend into frontiers still only vague-
ly perceived, and with genetic consequences that can only be
guessed at. And not content to have escaped the competition
for resources imposed on other living things, we have begun
to alter by pollution and to deplete by consumption those
resources upon which other life forms depend. This may not
176
EPILOGUE
be without a price. Most of us have become aware that de-

pletion of natural resources deprives us of species whose
beauty or grace or physical prowess we admire and whose ab-
sence from this planet we would mourn. What we are only
dimly beginning to perceive is that these species are in turn
the natural habitat of a range of microbial organisms with
whom they have lived for millions of years in peaceful equi-
librium. Deprived of their natural hosts some of these mi-
croorganisms, out of sheer desperation, have begun to jump
to humans where there is no such equilibrium, and may not
be for millions of years to come. The results, as we have seen
with the Ebola and AIDS viruses, can be disastrous.
Our minds have come to regard our bodies as something
more than a fancy vehicle for nurturing and transmitting
DNA, and have made us unwilling to let reproduction be, as
it is for all other living creatures, our only imperative, our
only impact on the world in which we live. We have become
thinking creatures who think about a great deal more than
DNA. As the story about the brain surgeon shows, the brain
through mind can even think about itself. But the mind con-
templating the brain—and thus itself— is a bit like looking
into a mirror with another mirror behind our back; it trig-
gers an endless array of front and rear images tapering off
into infinity. So when we try to think of the universe and our
own place in it, when we think about what defines us as
human, or about life and death, perhaps we should retain a
certain skepticism about our conclusions. We must remem-
ber that whatever notions we may hold about the impor-
177
EPILOGUE
tance of the brain as mind, these notions originated in the

mind as brain. In any other aspect of human affairs, this
would be considered a conflict of interest. It is a humbling
thought, but the human mind is not the power that drives
the universe. Whether we like it or not, the mind as brain
is driven ultimately by DNA, this bizarre molecule that is in
turn driven — mindlessly, we presume, yet somehow desper-
ately— to reproduce itself.
When we complete the dying process, every single cell
in our body will be dead, as nature intended. If we have done
her bidding, we will have passed on our DNA, packaged in
germ cells, to the next generation. That DNA may very well
be standing next to our death bed in the form of a son or a
daughter. The DNA in all the rest of the cells of our body—
our somatic DNA—will no longer be of any use; like the DNA
in the first redundant macronucleus a billion or so years ago,
it will be destroyed. To paraphrase an old biological saw, a
human being is just a germ cell's way of making another
germ cell — as is a cockroach; as is a cabbage. This is not a
very flattering way to explain ourselves to ourselves. We want
so desperately to be more than just a vehicle for DNA, and at
least transiently we are. Yet somatic cells will die at the end
of each generation, whether they are part of an insect wing
or a human brain. We may come to understand death, but
we cannot change this single, simple fact: in the larger
scheme of things, it matters not a whit that some of these
somatic cells contain all that we hold most dear about our-
178
EPILOGUE
selves; our ability to think, to feel, to love — to write and

read these very words. In terms of the basic process of life it-
self, which is the transmission of DNA from one generation
to the next, all of this is just so much sound and fury, signi-
fying certainly very little, and quite possibly nothing.
179
Further Reading
Books and Journals
"Adult Advanced Life Support." Journal of the American Medical

Association 268 (1992):2199.
"Adult Basic Life Support." Journal of the American Medical Association
268 (1992):2184.
Bell, G. Sex and Death in Protozoa. Cambridge University Press:
Cambridge, 1988.
Crowe, J. and J. Clegg. Anhydrobiosis. Dowden, Hutchinson and
Ross, Inc.: Stroudsburg, PA, 1973.
Dawkins, Richard. The Selfish Gene. Oxford University Press: Oxford,
1989.
Defining Death: Medical, Legal and Ethical Issues in the Definition of
Death. U.S. Government Printing Office: Washington, DC,
1981.
"A Definition of Irreversible Coma." (Report of the Ad Hoc Com-
mittee of the Harvard Medical School to examine the defini-
181
FURTHER READING
tion of brain death.) Journal of 'the American Medical Association

205 (1968): 337-340.
Gall, J. (ed.). The Molecular Biology of Ciliated Protozoa. Academic
Press: New York, 1986.
Gold, Michael. A Conspiracy of Cells: One Woman's Immortal Legacy
and the Medical Scandal It Caused. State University of New York
Press: Albany, 1986.
Grenvik, Ake and Peter Safar, eds. Brain Failure and Resuscitation.
Churchill Livingstone: New York, 1981.
"Guidelines for the Determination of Death." (Report of the Medical
Consultants on the Diagnosis of Death, to the President's
Commision for the Study of Ethical Problems in Medicine and
Biomedical and Biobehavioral Research.) Journal of the
American Medical Association 246 (1981): 2184-2186.
Halvorson, H. and A. Monroy. (eds.) The Origin and Evolution of Sex.
Alan R. Liss, Inc.: New York, 1985.
Hayflick, Leonard. How and Why We Age. Ballantine Books: New
York, 1994.
Kallman, F. J. "Twin data on the genetics of aging." In G.E.
Wolstenholme and C. O'Connor, (eds.) Methodology of the
Study of Aging. Little, Brown Co.: Boston, 1957.
Lamb, David. Death, Brain Death, and Ethics. State University of New
York Press: 1985.
Margulis, Lynn and Dorion Sagan. Origins of Sex. Yale University
Press: New Haven, 1986.
"Medical Aspects of the Persistent Vegetative State." (The Multi-
Society Task Force on the Persistent Vegetative State (American
Academy of Neurology).) New England Journal of Medicine 330
(1994): 1499, and 330: 1572.
"Persistent Vegetative State and the Decison to Withdraw or Withold
Life Support." (Council on Scientific Affairs and Council on
Ethical and Judicial Affairs of the American Medical Associa-
182
FURTHER READING
tion.) Journal of 'the American Medical Association 263 (1990):

426.
Potten, C. S. (ed.) Perspectives on Mammalian Cell Death. Oxford
University Press: Oxford, 1987.
Singer, P. Rethinking Life and Death. St. Martin's Press: New York,
1994.
Smith, I. R. Slepecky and P. Setlow. (eds.) Regulation of Procaryotic
Development. American Society for Microbiology: Washington
DC, 1989.
Walker, A. Earl. Cerebral Death. Urban and Schwartzenberg:
Baltimore, 1985.
Zaner, Richard M. (ed.) Death: Beyond Whole-Brain Criteria. Kluwer
Academic Publishers: Dordrecht, 1988.
Walton, Douglas N. Brain Death. Purdue University: Purdue, 1980.
Zwillig, R. and C. Balduini. (eds.) Biology of Aging. Springer-Verlag:
Berlin, 1992.
Original Scientific Papers
Allsopp, R., et al. "Telomere length predicts replicative capacity of

human fibroblasts." Proceedings of the National Academy of
Sciences 89 (1992): 10114.
Bayreuther, K., P. Francz, J. Gogol, and K. Kontermann. "Terminal
differentiation, aging, apoptosis and spontaneous transforma-
tion in fibroblast stem cell systems in vivo and in vitro." Annals
New York Academy of 'Science 663 (1990): 167.
Bernat, James. "How much of the brain must die in brain death?"
Journal of Clinical Ethics 3 (1992): 21.
Botkin, Jeffrey, and Stephen Post. "Confusion in the determination
of death: distinguishing philosophy from physiology."
Perspectives in Biology and Medicine 36 (1992): 1.
Clegg, James S. "Interrelationships between water and metabolism in
183
FURTHER READING
Artemia salina cysts: hydration-dehydration from the liquid and

vapour phases."/. Exp. Biology 61 (1974): 291.
Davis, M. J. Ward, G. Herrick, and C. Allis. "Programmed cell death:
apoptotic-like degradation of specific nuclei in conjugating
Tetrahymena." Developmental Biology 154 (1992): 419.
DeBusk, F. "The Hutchison-Gilford progeria syndrome." Journal of
Pediatrics 80 (1972): 697.
Denis, H. and J. LaCroix. "The dichotomy between germ line and
somatic line, and the origin of cell mortality." Trends in Genetics
9 (1993): 7.
Eiichirou, U., et al. "Preserved spinal dorsal horn potentials in a brain-
dead patient with Lazarus' sign: a case report." Journal of Neuro-
surgery76(l992):7lO.
Gillar, P. J., et al. "Progessive early dermatologic changes in
Hutchison-Gilford progeria syndrome." Pediatric Dermatology
8 (1991): 199.
Hastie, N., M. Dempster, M. Dunlop, A. Thompson, D. Green, and
R. Allshire. "Telomere reduction in human colorectal carcino-
ma and with aging." Nature 346 (1990): 866.
Hayflick, Leonard. "The cell biology of human aging." Scientific
American 242 (1980): 58.
Kalimo, H., et al. "The ultrastructure of brain death." Virchow's Arch.
B CellPathol. 25 (1977): 207.
Greider, C. and E. Blackburn. "Telomeres, telomerase and cancer."
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Keilin, D. "The problem of anabiosis or latent life: history and cur-
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Kerr, J., A. Wyllie, and A. Currie. "Apoptosis: a basic biological phe-
nomenon with wide-ranging implications in tissue kinetics."
Brit.}. Cancer26 (1972): 239.
184
FURTHER READING
Mantegna, R. N., et al. "Linguistic features of noncoding DNA se-

quences." Physical Review Letters 73 (1994): 3169.
Oppenheim, R. "Cell death during development of the nervous sys-
tem." Annual Review ofNeurosciences 14 (1991): 453.
Orstan, A. "How to define life: A hierarchical approach." Perspectives
in Biology and Medicine 33 (1990): 391.
Rosenberger, R. "The initiation of senescence and its relationship to
embryonic cell differentiation." Bioessays 17 (1995): 257.
Saunders, J. "Death in embryonic systems." Science 154 (1966): 604.
Skoultchi, A. and H. Morowitz. "Information storage and survival of
biological systems at temperatures near absolute zero." Yale
Journalof Biology and Medicine 37 (1964): 158.
Smith-Sonneborn, J., M. Klass, and D. Cotton. "Parental age and life
span versus progeny life span in Paramecium."/. Cell Science 14
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Yarmolinsky, M. "Programmed cell death in bacterial populations."
Science 267 (1995): 836.
185
Index
Accidental cell death 61, 172 Bacteria 55, 138

Advance directive 122, 130, Bernat, James 121
132, 165 Blastocyst 91
Advanced cardiac life support Botkin, Jeffrey 122
(ACLS) team 23 Bradycardia 106
Algae 59 Brain 151-156
Anaerobic metabolism 163 anatomy of 108
Antibodies 41 death 105-134
Apallia 107 death standard 110
Apoptosis 34, 35, 172 Brainstem 107, 113, 119, 126,
radiation induced 40 133
and senescence 88—90 Brine shrimp 144
Apoptotic bodies 36
Anemia salina 144 Caenorhabditis elegans 47, 50,
Asexual reproduction 62 88
ATP (adenosine triphosphate) Cancer 103
12, 16, 139, 163, 167 Catastrophic health care 132
Atrioventricular node 10 Catastrophic theory of aging 80
Autoclave 141 Cell Theory 6
Axon 162 Cells
187
INDEX
origin of 4—6 Dendrite 163

structure of 6; 9-14 Differentiation 91
suicide of 32-51 Dipicolinic acid 140
Chromosomes 58, 101 Diploidy 58
Ciliates 66 DNA 7, 12,33,40,43, 57,
Coma 107,115-116,123, 160 104, 155, 172, 175
Conjugation 64, 70 aging of 81
Conroy, Claire 127 in cysts 143
Cortex (brain) 107, 117, 120, in spores 140
126 replication of 71, 157
CPR (cardiopulmonary repair enzymes 81, 100
resuscitation) 20, 24, 110, segregation of 68
124,159 viral 150
Creatine phosphate 163, 167
Cryptobiosis 137-149, 164 Embryos
CTL (cytotoxic T lymphocyte) cell death in 29
41 growth in 98
Cyanobacteria 55 Embryonal stem cells 91, 98
Cysts 139, 143, 144 Encephalon 107, 113, 117, 120
Cytokines 49 Endocytosis 59
Endoplasmic reticulum 12
Dawkins, Richard 176 Endosymbiosis 59
Death Energy, interaction with
accidental structure 147
brain 105-134 Eukaryotes 58
as default state 38, 50 Euthanasia 129, 133
DNA as beneficiary of 93 Evolutionary tree 56
genes 99, 102
origin of 53-77 Fatty streak 15
programmed 28, 48, 76, 97, Fertilization 72
172 Fibroblasts 18, 36, 83-88, 101,
represser genes 168, 174
of spores 142 Fibrillation 21
Defibrillation 22, 64, 110 First-response team 21
188
INDEX
Fission 62 Macronucleus 69, 82, 87

Macrophages 18, 28, 36,41
Gene therapy 176 Meiosis71,81
Gartler, Stanley 96 Memory, immunological 39
Genetic code 157 Messenger RNA 12
Genome 98 Metabolism 136
Germ cells 74, 79, 82, 178 Micronucleus 69, 82, 87
Gey, George 94 Mitochondria 12, 13, 16, 36,
60,143,150,168
Haeckel, Ernst 29 Monera 55
Hand, development of 29 Monoploidy 58, 71
Hayflick, Leonard 86, 94 Morowitz, Harold 145
Hayflick limit 89, 93, 174 Mortality, acquisition of 90-91,
HeLa cells 93, 102 98-104
Hepatitis B 45 Multicellularity 8, 61, 74, 118,
Heart attack 19 171
Histones 57 Mutations
Homeostasis 9 accumulation of 100
Hughes, Richard 125 repair of 66
Myocardial cell 10
Immunopathology 47 Myxobacteria 57
Immortality 68, 91,97
Infarction 19, 161 Necrotic cell death 27, 173
Ischemia 15, 161 Nerve fibers 37
Nucleus (cell) 10
Kelp 59
Killer T cell 41 Ontogeny 29
Organ transplantation 111
Lacks, Henrietta 93, 174 Osmotic pressure 14
Life, definition of 148
Living will 122, 165 p53 102
Lymph fluid 9, 15,37,41 Paramecium 59, 66-72
Lymphocytes 39 Persistent vegetative state 109,
Lysosomes 13, 17, 37 114-117,133,164
189
INDEX
Phylogeny 29 119,172,175,178
Plasma membrane 13, 35 Spores 139-142, 149
Pluripotency 98 Stroke 161
Polyploidy 61 Suicide, in cells 32-51
Positron emission tomography CTL-induced 43-47
164 radiation-induced 40
Post, Stephen 122 in embryos 29
Progeria 83-84 Surrogate decision making 123,
Programmed cell death 28, 48, 128, 130, 131
172 Synapse 163
Prokaryotes 57
Protista 57 Telomerase 101
Protoctista 57 Telomeres 58, 101
Pumps, membrane 13, 16, 150, Thalamus 126
162, 164 Tetrahymena 87
Tetraploidy71
Quintan, Karen Ann 123 Totipotency 92, 99
Trehalose 142, 144
Ribosomes 12, 36, 140, 143,
150, 168 Uniform Determination of
Death Act 112, 123
Schwann, Theodor 6
Senescence 63, 67, 77, 79-104 Veatch, Robert 121, 133
Sex 65, 172 Viruses 41, 94, 149-151, 156
and death 62-77
origin of 65 Wanglie, Helga 129
Sexual reproduction 63 White blood cells 17, 39, 168
Singer, Peter 174 "Whole-brain" death 113, 122
Sinoatrial node 10
Skoultchi, Arthur 145 Zygote90
Somatic cells 74-76, 100, 103,
19O
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Sex and the

OXFORD UNIVERSITY PRESS

New York Oxford

Copyright © 1996 by Oxford University Press, Inc.

Library of Congress Cataloging-in-Publication Data

A number of people have worked hard to help me

As promised so clearly and unapologetically in the

journals. But thanatology focuses on the psychosocial aspects

increasingly viewed as one of the most important aspects of

individual cells and into the molecules and atoms of which

If you know not how to die, do not trouble yourself. Nature

The average adult human being is composed of

being alive than others? What do we really know about these

today as bacteria, yeast, amoebae, and many other single-cell

exception — must die. We will discuss this exception a bit

of staining techniques. Identification at the structural level

unless we insist on lying under the sun for hours on end

result, human cells are more vulnerable to threats from the

Figure 1. Internal organization of a prototypical contractile cell. In this

cells—the insulin-producing beta cells of the pancreas, for

Conversely, the concentration of water outside the cell is

Although it doesn't know it yet, the myocardial cell we

termittently, the cell senses that something is terribly wrong.

from the nucleus pile up unread. Partially finished products

invaders. So wherever they go, the warrior cells are accom-

way when he was literally brought to his knees by a horren-

She struggles to turn her husband over on his back. She

at different times, without the integration needed for effec-

resistance of the chest cavity to the electrical shock just given,

at least two additional minutes to complete. Finally the tube

heart muscle—has this morning's attack inflicted? Will his

A Second Face of Death

Let us therefor consider howfarre and in how many waies

The death of a myocardial cell described in the last

one of the many toxins released by bacteria and other path-

dividual fetus in the womb recapitulates the biological his-

sis. They do not die because their blood supply is interrupt-

but it is not in response to sorrow or despair, nor is it a form

been destroyed, the cell cannot reverse course; it cannot alter

modest assistance, can continue to function more or less nor-

like when seen through a powerful electron microscope.

tissues, bathed as always in nutrient- and oxygen-filled

vous systems communication line to the targeted cell for life.

of cells they will never use, shunting the unselected into

radiation. This phenomenon has long intrigued and puzzled

promised. This is the specific task of a highly specialized cell

And then one day a dozen or so years ago, someone de-

extraneous cells in the developing fetus — has embedded in

such harmless microorganisms from the body, the damage

acute form of the disease the infection is often completely

it to commit suicide. Cells also commit suicide in response

beginning to identify some of the genes that control these

obviously of great importance to nature. We shall return to

Sex, Segregation, and the

For man that is born of woman is of few days, and full of

sense of the answer to this question, we must go back in time

certainly, it did not arrive on the scene until a billion or so

Figure 4. Major evolutionary groups. All classifications of living things

tionary event of major proportions. Oxygen is a deadly, cor-