The average adult human being is composed of something more than a hundred trillion - 10¹⁴ - individual 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 organism like a human being, are some cells more important for 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 carbon- and nitrogen-based compounds that could be readily converted, under the influence of the tremendous thermal, 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 explaining 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 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 wander 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 materials contained in the "primordial soup" - the collection of bioorganic molecules generated in the high- energy reactions 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 nature’s practice in "getting it right." And each of these near-perfect cells - with one exception - must die. We will discuss this exception a bit later.

The idea that plants and animals are made up of individual cells that correspond to and are ultimately derived (in an evolutionary sense) from the free-living, single-cell microorganisms that still permeate our environment was inspired 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 animals 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 nineteenth century of chemical stains that could make the different 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 of staining techniques. Identification at the structural level of other parts of the cell took longer, and association of structures 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 whose functions are not entirely certain.

Cells are the smallest living units making up our bodies. They are incredibly tiny; ten thousand of them clustered together are just visible to the unaided eye. Yet every cell contains 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 reproduce the entire being of which it is but the hundred-trillionth 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, 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 second 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 living. Cells that united to become multicellular also became soft. Once they accustomed themselves to their new environment and a life of relative ease, cells lost their toughness, their ability to cope with conditions less than ideal. As a 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 organisms 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 environment. The permissable 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 vessels from which oxygen and nutrients diffuse into the surrounding 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 function. Imagine for a moment that we are actually inside a living 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 anything 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 contract 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 bungie 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 myocardial cells making up the wall of the heart. For a brief, instant, 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 dominated by a large, walled-off compartment called the nucleus. If you look carefully, you will see what appear to be little round portholes all over its surface. These are where molecules 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 single characteristic of the cell and the instructions for operating 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 discernable function or meaning, and has been labeled "nonsense DNA".

The machinery for operating the cell is found in the liquid cytoplasm filling the cell outside the nucleus. These humming 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 ribosomes strung together by an almost invisible thread of messenger RNA (mRNA). The mRNA is in effect a xeroxed set of instructions, 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 convoluted 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 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 contractile 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 mitochondria snugged up next to them for efficient delivery of the large amounts of ATP needed to carry out their repetitive contractions. 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 cholesterol, to keep the watery interior of the cell completely separate 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 sustain life. And the concentration of these molecules inside cells is often much higher than the concentration outside. Conversely, the concentration of water outside the cell is much higher than the concentration of water inside. As a result, 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 fluids, and much higher levels of potassium ions. Cells use separate sets of energy-driven pumps to maintain these ionic gradients. If any of the pumps shut down, the cell will quickly 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 identical 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.

Although it doesn't know it yet, the myocardial cell we are in is about to die. It will die because of myocardial ischemia, 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 debris. In this case the debris is a complex mixture of fat, cholesterol and dead blood cells that has been building up inside 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 intermittently, 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 particular food and oxygen. The mitochondrial ATP generators, responsible 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 critically 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-diminishing supply of ATP. It is no longer a question of function; it is now a matter of survival or death. All other energy-driven 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-synthesizing machinery stands everywhere idle in the cell; messages 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 transport 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 distort 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 invaders that can cause disease and death. But these warrior cells do not always prevail, and even when they do there may be incredible carnage, with as many dead white cells as dead invaders. So wherever they go, the warrior cells are accompanied 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 floating by in the lymph fluid alert the macrophages to the presence of death, and they begin trudging upstream, working their way through the ever increasing density of floating debris 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 removing 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 nutrients 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 of death with thick layers of pale scar tissue. When all is finished the macrophages will slip away into the lymph to rejoin 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, 62 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 hallway floor of his home; he has suffered a major heart attack. It is not his first. His initial heart attack, two years earlier, involved ischemia to a significant portion of heart muscle that subsequently became infarcted - converted into dead, functionless myocardium overridden with whitish scar tissue. The pumping efficiency of his heart was reduced considerably, 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 hallway when he was literally brought to his knees by a horrendous 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 collapsed the rest of the way to the floor. Like the majority of heart attacks, his came early in the morning, at a time of relative 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 hallway. 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 sweating profusely, his eyes closed. She calls his name, shaking him and slapping his cheeks. He does not respond; he is unconscious. 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 shaking 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.

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 respiration. She moves over him and feels for the tip of his sternum - 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 repeating 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 information 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 uncoordinated 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 at different times, without the integration needed for effective pumping. As a result, there is no regular pulse or recognizable pattern of spiking on the ECG 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 important parameter for saving lives. It has been nearly eight minutes 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 atrioventricular nodes will be able to reestablish a coordinated cardiac rhythm.

But a glance at the monitor shows the same erratic pattern as before. The defribrillator, its paddles serving as electrodes to the man’s body, analyzes the heart rhythm and the resistance of the chest cavity to the electrical shock just given, and adjusts output automatically if further shocks are indicated. They are. After the command to stand clear is given once again, current is quickly applied a second time, and then a third, before something approximating a normal heart rhythm begins to appear. The defibrillator screen flashes a message that no further shocks are needed. One of the firemen 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. 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 paramedic wants to place the tube into the trachea in order to deliver 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 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 paramedics administer drugs through the i.v. line started earlier, to help stabilize him for the ride to the hospital. The breathing 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 paramedic 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 followed by defibrillation and intubation, their patient would have been dead many minutes ago. But he is still unconscious, which worries the paramedics. And he was not breathing properly when they arrived. 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 heart muscle - has this morning’s attack inflicted? Will his heart be able to withstand much longer the cumulative destruction of two major attacks?

We will rejoin our patient a little later, once he has reached the hospital. He will be subjected to further emergency procedures to stabilize his condition, and then examined 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.