How Cells Die
It had been the longest of months—in both the best and the worst possible ways. Brockton is a small town about a half-hour drive south of Boston, but in many ways it seems a world apart. As you move away from Boston, you can actually see rust accumulate on bridges, signboards, and fire hydrants. Boston carries a tasteful level of agedness, akin to a hint of silver hair. The red brick Federalist-style apartments of Back Bay, many built in the colonial period, have just the right amount of decay, which gives them a deep and rich texture. With Revival- and Georgian-style buildings intermixed, Boston is just rough enough to be photogenic. Brockton, on the other hand, is a town falling apart. Crooked goalposts stand half erect in fields with tall grass that might not have seen a game of football in decades. The town is awash in violent crime and drugs.
The town of Brockton is served by a community hospital that mirrors many of the characteristics of the town it is located in. Medicine residents from my program would go to the intensive-care unit (ICU) in that hospital for an away rotation, and it was an experience of legendary proportions. Unlike the large academic referral center we were used to, with an abundance of nurses and doctors, the Brockton ICU was run predominantly by the residents even though the patients there were sicker in many ways. In the primary hospital where I was training, there was a surgical ICU, a neurological ICU, a cardiac ICU, a trauma surgical ICU, and a bevy of medical ICUs, but there was only one ICU at Brockton, leaving the care of patients with a host of acute conditions in the hands of the medical residents and the supervising physician.
It was a Sunday, Super Bowl Sunday no less, and it was my last day in Brockton. The Patriots had lost the week before, so my interest was somewhat muted, but still, it was Super Bowl Sunday. I was scheduled to be there until seven in the evening and it would take me an hour to get back to Boston with the traffic, which would mean I would miss a large chunk of the game. But this Sunday was an almost miraculously quiet day. My team was done with rounds by noon, and we got no new patients afterward. It was so relaxed that I did the unthinkable: I asked my team who was going to be there overnight, whether I could call the shuttle early if we continued to have a quiet day. We had a deal. When the clock struck three, the ED was not buzzing, all our patients were well behaved, and there was no one headed up from the wards, so after checking again with the team, I called the shuttle service to come pick me up at five. I called my wife, ecstatic that I would be done early, and asked her to call our friends so that we could actually have the Super Bowl party she had so wanted to host.
It wasn’t long after I hung up that my pager buzzed. There was a medical emergency on one of the wards. I picked up my stethoscope and shuffled toward where the emergency was. When I got there, the whole ward stank of human excrement. One of the nurses directed me toward a room outside which a large crowd had gathered. I made my way through the throng and found that there were three nurses in the bathroom struggling with a patient who didn’t seem to be fully conscious. He was slouched over on the toilet seat, totally naked, and the entire bathroom floor was covered in black and bloody feces. The bathroom was very small, and the patient was at least six and a half feet tall and must have weighed at least three hundred pounds. The nurses were trying in vain to lift him up, while a few others were attempting unsuccessfully to get his bed into the bathroom. There was complete chaos, and no one had any idea what was going on.
The man was barely breathing, but he had a pulse. I quickly realized two things: There was no way the bed was getting into the bathroom, and there was no way we could get the patient into the bed. I asked one of the nurse assistants to grab a wheelchair. He brought the wheelchair right up to the bathroom door, and I carried the patient with the nurses from the toilet seat to the wheelchair. Given how sick he was, I knew I didn’t even have the time to fully examine him. I had the room emptied so that we could get the wheelchair out of the bathroom and roll the patient to the ICU. One of the nurses threw a bedsheet over his naked body, and we wheeled him up, his head slumped on his chest, to the ICU. He was drooling all over his chest, he was barely breathing, and in his wake he left a long trail of blood and stool that smeared the entire hallway behind him. The resident who was with me took a picture of the hallway with his smartphone. Neither of us had ever seen anything like it.
Once he was up in the ICU, it took about six people to transfer him from the wheelchair to the bed. One of the nurses who had been taking care of him on the ward and had accompanied him upstairs to the ICU told us that he was forty-something and had presented with some bleeding from his rectum last night, but it was only a small amount and he had never experienced similar symptoms before. The team on the ward had actually been thinking of sending him home later that day. The nurse had already called his wife, who was now on her way thinking she was taking him home.
The man, who had been very somnolent until now, started to wake up. But this was not a good thing. He was in shock and was completely delirious. He started thrashing around and pulling the IV lines from his arm. He was immensely powerful, and it took one person per limb to keep him from falling over. It became clear to us very quickly that his risk of choking was high and there was no way we could guarantee patency of his airways without intubating him and having him breathe with the ventilator.
I made my way to stand at the top of the bed and used one hand to keep his head planted down. He was looking me straight in the eye, grunting, with a towel in his mouth preventing him from biting down on his tongue. His blood pressure was in the tank and he had lost almost half his total volume of blood. He was in dire, dire straits. My eyes darted away from the patient’s as I looked for the equipment I needed to be able to intubate him. A nurse on the other end of the room had a large green container, so robust it would fit right in at a bomb shelter, with all the tools I needed. With the supervising physician by my side, I picked out the appropriate-size laryngeal blade, which was basically a large tongue depressor made out of metal. I took the blade out and opened it up to be in its usual L-shaped configuration. All the while I was running through my head what I was going to do. I had intubated patients in the past, but never in such a boisterous environment. My attending, an anesthesiologist with Jedi-master skills, stood by me and didn’t even hesitate in handing the blade over. Most attendings would get nervous and take over the intubation rather than wait for the trainee to mess around, but not him.
Sticking a tube down a person’s throat is actually way harder than it may seem. The last thing you would want to do (although it happens frequently enough) is go down the esophagus and into the patient’s stomach rather than down the trachea, which leads to the lungs. Blocking the way is the tongue, which extends much farther down than most people imagine. And then there is the small issue of the epiglottis, a trapdoor-like flap, which covers the trachea to prevent food from going down the windpipe when we speak or breathe. And then once you make your way past the epiglottis, you need to go past the vocal cords, which hang like fluttering curtains right at the top of the trachea.
Standing at the head of the bed, looking at his upside-down face, I signaled to the nurse holding a syringe full of milky propofol to inject the anesthetic. Even in the maelstrom, she was careful, flushing the IV with some saline, injecting the anesthetic, and then flushing again. After the propofol had been injected, we continued to hold the patient down, awaiting the relaxation of his muscular tone. Two minutes passed and we realized we needed something stronger, so we injected a paralytic. His head, which had been thrusting against my forearm, relaxed down; his eyes, which had been staring at me with unspeakable grit, now just stared at the ceiling. Everyone let go and the patient became limp. He stopped breathing, and the respiratory therapist continued giving him oxygen through a bag mask. As soon as the patient’s oxygen levels hit 100 percent, the race was on: I had only seconds to be able to intubate him before his oxygen level dropped.
I passed the laryngeal blade past his tongue and then used it to push the tongue down, lifting his chin up, in the hope that I would glimpse my goalpost—the vocal cords. But his tongue was beefy, and even when I flexed my wrist to the maximum, I could barely see them. I didn’t want to just blindly thrust the tube down, which I was anxiously holding in my other hand. My supervisor, on the other hand, was now starting to get impatient. He told me that I wasn’t flexing my wrist enough. I looked over my shoulder and saw that the patient’s oxygen level was already down to 80 percent. I snaked my blade farther down his throat, almost lifting his head off the bed, and there it was—the thick rim of the vocal cords, pale like chapped lips, surrounded by membranes laden with small capillaries. I grabbed the J-shaped breathing tube, curved it down his throat, and jabbed it through the cords into the black beyond. I pulled out the metal wire that was maintaining the tube’s form, and the respiratory therapist connected the bag mask and inflated the cuff in the tube that prevents air from leaking. Next, all of us looked for the telltale signs of the tube going down to the stomach instead of the lungs. The respiratory therapist squeezed the bag, and thankfully it was the lungs, not the belly, that inflated. A nurse put her stethoscope on the belly and heard no breath sounds there from the mask. This man was not out of the woods yet, not by a mile, but I looked up, my visor fogging up, my scrub cap sweaty; I was relieved that at least his airway was secure. I took my gloves off and saw the aides outside the room waiting to take over, with bags upon bags of blood, platelets, and clotting factor.
I didn’t even make it out of the room before my pager rang, and before I could even look at it, the overhead speaker blared: “Code blue. Hospital lobby.”
Torn, I looked at the other resident, who told me to run down and that he would hold the fort in the ICU.
There is an etiquette to running in the hospital; I avoid running under almost all circumstances, because it can make other people panic and can ruin one’s composure. The rule I have for myself is that it’s okay to run in stairwells where there are no patients or family members, but not in corridors. Which is why I went for the first stairwell I could find so I could just flat-out run.
I emerged from the stairwell on one end of the lobby and walked toward the entrance, where there was a large crowd of people gathered. Most appeared to be people who were visiting family members in the hospital and now were captivated by some kind of commotion. As I got closer I could hear a woman wailing and crying. A wall concealed the scene itself, and as I approached the entrance I became increasingly full of dread as to what I would find. Just before I caught a glimpse, a child cried out, “Is Mommy gonna die?”
Right in front of the double doors that led into the hospital, a young woman lay on the ground, seemingly unconscious. Next to her, a paramedic was kneeling, and as soon as he saw me, he told me that she still had a pulse but that she had just had a seizure. The woman, curled on her side, was very obviously pregnant. It had to be a seizure from eclampsia, I thought. I laid her flat on the ground to make sure she was breathing fine, which she was. But the commotion was still ongoing. Her mother was going completely berserk, pulling her own hair, screaming, and clearly scaring everyone around her. The crowd, now growing as more doctors and aides converged, was reacting more to the mom than they were to the woman, who was miraculously quite stable at present. The mom was even distracting the emergency-room physicians who had come to help the young woman, but then one of the aides told the mother more sternly than I would have, “Hey lady—keep it together.”
I took the young woman to the emergency room, ensuring that she would have someone responsible for her, fulfilling my role as the emergency backup. With that settled, it was time for me to head back to home base. I looked at my phone; it was overflowing with unanswered texts and phone calls. On my way back to the ICU, I called the shuttle driver who was waiting outside and apologized, telling him that there was a patient in critical condition and that it would be great if he could pick me up once the patient was stable enough for me to go home.
As soon as I got back to the ICU, I made a beeline for the room of the patient I had intubated about fifteen minutes ago. The nurse promptly handed me the kit for placing a central line: there weren’t enough IV lines to get him all the blood products he needed. The other resident was busy with other patients, so I grabbed the package and dove back into the vortex. We started with a large IV line in the femoral vein in his groin, then placed another in his chest and an arterial line in his wrist. It was as if I needed to perform all the procedures I had learned during residency in one day and on one patient. By the time I got done, it was clear that it was unlikely that the man would ever wake up again. While he was breathing on a ventilator and his heart was beating, we weren’t sure whether he was alive anymore or whether he was brain dead or whether he was somewhere in between.
When I first started residency, signing off was very difficult. It was hard to shift responsibility for a patient I had been taking care of to someone who was just covering overnight. Any amount of verbal communication or any number of e-mail signouts would still leave me feeling that I had somehow left my patients hanging. When you are taking care of a patient, you feel that no one else might be able to manage the patient as well as you can, based on the fact that you know the patient the best.
By this time, though, in the third year of my residency, I had become seasoned enough to know when to ease off. I could stay there as long as I wanted, but that was probably not going to change the outcome. Looking at the man in front of me gave me perspective, though: he had gone from having a completely normal life yesterday to having ten additional points of entry in his body and his ability to make it through the night under question. It made my own worries almost comical in comparison. I was going to miss much of the Super Bowl, but as I looked at the patient’s wife in the waiting room on my way out, it was clear that there were many, many people in this world who had a lot more riding on this night.
I walked down to the lobby, which was much quieter than when I was last there, and saw the shuttle, a black Lincoln sedan, waiting outside.
“Did he make it?” the driver asked, once I had gotten in and started eating the salad I had picked up from the cafeteria.
I looked in the rearview mirror, and the driver was looking back at me. I was a bit surprised, but not in a bad way. “Did who make it?”
“The guy you told me over the phone about, who was dying.”
I suddenly remembered telling the driver on the phone that I was going to be late.
“I am not sure,” I told him.
His eyes moved away from mine through the mirror and back to the road.
“Death,” he said, “is such a primitive concept.”
Doctors experience death more than any other professionals do—more than firefighters, policemen, or soldiers—yet we always think about death as a very concrete construct. It’s a box on a checklist, a red bar on a chart, or an outcome in a clinical trial. Death is secular, sterile, and singular—and, unlike many other things in medicine, incredibly binary. So it was interesting to think of death more as a concept and a process than as a fact and an endpoint.
Looking back now, I can say that the driver was right on many counts. Perhaps the most primitive aspect of death is how we respond to it, how we spend most of our lives imagining it away, how we fear it as some sort of unnatural schism in space-time. Every time we talk about death, the food seems terrible, the weather seems dour, the mood sullen. Every time we think about death, we get so depressed we can’t hold a meaningful thought in our heads. Many families talk about death only after their loved one is in the ICU, hooked up to more gadgets than Iron Man.
When I first thought about writing a book about death, I went up to my wife, a civilian, and told her about it. She seemed bemused. Just hearing the “d” word made her feel ghastly. I was surprised by her reaction, but since then I have become a bit more used to getting a similar reaction from others.
There are many things that, at any given moment, are deemed taboo subjects by society. Sex is perhaps the first thing to come to mind. Money, at least in some circles, is another. But even sex and money are things whose degree of tabooness varies from culture to culture and from time to time. Talking about death, though, has remained the hardest to pick of all forbidden fruit.
What makes death so difficult to talk about? The difficulty is due in part to social dogma and in part to tradition. The very nature of death, the mystery that surrounds it, breeds uncertainty. Uncertainty breeds fear, and contrary to general perception, never has death been as feared as it is today. The more medicalized death gets, the longer people are debilitated before the end, the more cloistered those who die become, the more terrifying death gets. The last century has given most people the gift of a prolonged life span, but the increased expectation of a long life has made an unexpected road bump all the more hard to digest. Those who know they are going to die early feel cheated of the promise of old age. The only way to make any real change is to tear away the vines of terror that creep up our legs whenever we talk about death and dying.
Conversations about death have become more ineffectual and detached from reality. Death is more commonly used as a political weapon to stir up fear among voters and constituents than it is accepted as an eventual fate of all living organisms. The fear of death has been used to instigate wars, form religions, and make a segment of society rich beyond their dreams, but before this century, we had almost no actual understanding of dying. This lack of understanding, however, has never stopped death from being extremely divisive, and to this day our comprehension of death remains stunted.
On the other hand, the driver couldn’t have been more wrong. Death is as ancient as life itself, and you might even argue that death precedes life—for what was there before life, anyway. But the last century has seen death evolve and morph more than any previous time in human history. Not only have biomedical advances changed the ecology, epidemiology, and economics of death, but the very ethos of death—in the most abstract possible sense—has changed. Far from being clearer, the line between life and death has become far more blurry. These days we can’t even be sure if someone is alive or dead without getting a battery of tests. While death may be a primitive concept, most people have very little idea what modern death is all about. There were so many things I wanted to say to the driver, but, at least that day, I chose to just sit back and listen.
* * *
AFTER REMAINING MORE or less static over many millennia, death changed on a fundamental level over the course of a century. Modern death is nothing like what death was even a few decades ago. The most basic aspects of death—the whys, wheres, whens, and hows—are fundamentally different from what they were at the turn of the last century.
To understand why we die, it’s important to understand how we come to live at our most granular level. Human beings are made up of billions of cells of all kinds, each of which possesses life, but not conscious life. We also carry within us gazillions of bacteria that mostly reside in our intestines. In fact, the average human contains ten times more bacteria than human cells.1 We know now that humans share at least forty genes with bacteria, and are thus distant cousins in a strange way.2 Each of us, therefore, is like a mother ship carrying denizens, both human and bacterial, that together constitute an interdependent, fully functioning sentient colony with an identity that is not merely existential but physiological.
While death might certainly appear to be simpler than life, our understanding of how cells are formed predates our understanding of how cells die by at least a century. The process of cell division, wherein one cell divides, forming two identical daughter cells—mitosis—was first described in 1882 by the German physician scientist Walther Flemming. Meiosis, wherein one cell divides into two unique cells necessary for reproduction, was also discovered by two Germans, Theodor Boveri and August Weismann, in 1887.3 Therefore, the process whereby a new cell forms was well appreciated as early as the late 1800s.
But not only was cell death not well studied until fairly recently, it was rarely witnessed. Pathologists, microbiologists, and people from all backgrounds peered down microscopes, but rarely saw a cell in the process of dying, although cells being formed were seen routinely on slides. It was conveniently assumed that cells were continuously dying to accommodate all the cells that were constantly being made. Recent advances in the field of cell biology not only have improved our understanding of how cells die, but have illuminated the life of cells more than almost any other recent discovery in this area.
The answer to one of modern biology’s most vexing questions would come from the unlikeliest of sources. Caenorhabditis elegans is a nematode, the smallest of roundworms, transparent and only about a millimeter in length.4 It minds its own business, staying mostly in the soil, feeding mostly on a diet rich in bacteria, and never infects humans. While it lacks a heart and lungs, it does have many organs similar to the organs of larger animals, such as a nervous system, and a fully loaded reproductive system with a uterus, ovaries, and even the equivalent of a penis. Interestingly, 999 out of 1,000 of these worms are hermaphrodites, with only 1 out of 1,000 being a “true male.” The hermaphrodite doesn’t really need a male for insemination, although given a choice it tends to prefer male semen to its own or that of another hermaphrodite. The typical C. elegans worm, barring any major catastrophe, lives for two to three weeks. This worm is a hardy being, and, in fact, C. elegans worms survived the Columbia space shuttle disaster, in February 2003.5 When the end does arrive, in a scene with no small amount of drama, the worms emit a blue light just prior to their demise.
What makes these worms essential to science is their unique and relatively simple development. They demonstrate a phenomenon known as eutely, in that their adults have a fixed number of cells, and that number is specific to that species. Once a baby worm is born, it grows in size by cell division. When the cells reach a total of 1,090, they stop dividing. After this specific number of cells is reached, future growth is achieved just by enlargement of existing cells. In the hermaphrodites, though, a select few cells are automatically terminated. It is the genetically predetermined culling of 26 cells in a millimeter-long worm that has now elucidated how cells decide, or are nudged, to commit suicide.
The life cycle and cellular programming of this roundworm’s cells was investigated first in Cambridge, United Kingdom, and subsequently in Cambridge, Massachusetts, in the United States. Sydney Brenner, a South African biologist, set up his developmental-biology lab in Cambridge, UK, where, along with John Sulston, he analyzed the entire genetic makeup of C. elegans.6 It was around this time, in 1972, that the name apoptosis was proposed by scientists John Kerr, Andrew Wyllie, and Alastair Currie for this “hitherto little recognized” phenomenon of cell death.7 “Apoptosis” (pronounced “APE oh TOE sis”) is a Greek word, used to describe the falling of leaves from trees, or petals from flowers. Brenner and Sulston were joined by Robert Horvitz, who later established a lab at the Massachusetts Institute of Technology, where he continued the work he had started across the pond. In 2002, Brenner, Sulston, and Horvitz were jointly awarded the Nobel Prize in Physiology or Medicine for their discoveries, which revolutionized our understanding of life as much as they did our understanding of death.
We know now that cells die mainly from three mechanisms: apoptosis, necrosis, and autophagy.8 All three have important metaphysical implications.
The ugliest and least elegant of cell deaths is necrosis. The word is derived from the Greek word “nekros,” which means “corpse,” and the process occurs when cells are suddenly deprived of nutrients and energy. When blood flow is interrupted, as it is to the brain after a stroke or the heart after a heart attack, the affected cells undergo necrosis. Necrosis starts with the membranes of cells becoming increasingly permeable. Fluid enters the cells from outside, swelling up the cells and their contents in a grotesque fashion until the cells rupture, spilling their contents into the extracellular space. This wanton destruction is also purposeful, in that the first cells to necrose serve as sentinels, warning the rest of the body about the inciting event, whether it be an injury, extreme heat or cold, or a poisonous substance.9 The human body is always being patrolled by the immune system, always looking out for foreigners. The contents of the cells represent the hidden self, given that they always remain cloistered within the cells, and they are perceived as alien if ever they emerge into the sera. Since the body is not used to seeing these molecules outside the cell, their release alarms the body, which promptly sends in immune-cell reinforcements.
Activation of the immune system initiates the salvage, rescue, and repair program. The cells that necrose are beyond help, but the immune system helps to keep the fire from spreading to unaffected parts. While necrosis was initially thought to be an accidental or uncontrolled form of death, recent advances have shown that it, too, is carefully orchestrated and can be selectively triggered and halted by molecular pathways.10
Autophagy is the process wherein the cell consumes (“-phagy”) itself (“auto-”) or parts of itself. A harbinger of death, autophagy is as essential for life as it is for death. Autophagy is used by the cell to convert its own defective or redundant components into useful nutrients during times of scarcity. Unlike necrosis, which occurs after a complete cessation of supplies, as in a heart attack, autophagy occurs in the presence of a relative scarcity, as in heart failure. When food is limited but still present (unlike when necrosis occurs), the cell tries to shut off unnecessary machinery or get rid of damaged goods by creating small autophagosomes. The autophagosomes are small bubbles that contain toxic materials. These autophagosomes engulf whatever machinery or materials the cell wants to dispose of and transform them into useful nutrients. Widespread autophagy, however, can result in autophagy-associated cell death.
If anything, autophagy is an essential means for the cell to stave off death, as it can be used to consume damaged cell parts such as mitochondria, which are the turbines that convert oxygen into pure energy for the cell and can induce cell death if they burst. An inability to perform autophagy actually accelerates the death of the cell instead of abating it.
Finally, then, we come to apoptosis, perhaps the most important and interesting form of cell demise. In necrosis, a defect in the integrity of the cell membrane is one of the first steps to occur, but in apoptosis the cell membrane remains intact until the very end. Apoptosis, in spite of its complexity, occurs much faster than mitosis—about twenty times faster—which might account for its less frequent sightings on microscope slides. The entire process takes place over hours.
When a cell is about to undergo apoptosis, it becomes more rounded and draws away from other cells. A cell is asked to terminate itself after it is tagged by the grim reaper of the cellular realm—tumor necrosis factor alpha, aka TNFα—which arrives by a cell’s side and attaches to a receptor on the cell membrane. This is the molecular version of a kiss of death, activating the so-called death receptor pathway. The cell then dutifully follows its fate and triggers caspases. Caspases are enzymes that live within cells and usually help out with housekeeping, repairs, etc. But when activated by death signals, they initiate a cascade of events that results in a cell dying quietly within itself. Another way cells undergo apoptosis is when mitochondria, after detecting damage to the cell, release proteins from within the cell to signal the initiation of apoptosis. One of these proteins, aptly named “diablo,” activates the killer caspases, ringing the death knell.
The cardinal feature of apoptosis is that the cell’s organelles start to shrink. The cell membrane remains intact, never exposing the hidden self and therefore not taxing the immune system. Small blebs start breaking off from the membrane, and the cell disintegrates into smaller chunks. Apoptosis is frequently compared to the “controlled demolition” of a skyscraper, where it is very important to ensure that surrounding buildings are not damaged.11 By a complex mechanism, when a cell is sentenced to die, phagosomes are alerted. Phagosomes are small cells that serve to digest cell components; they are unlike autophagosomes in that they target other cells rather than the cell they originate from. The signal emitted designates the apoptotic cells as separate from the true self and therefore kosher for consumption.
Life and death at our most basic, cellular level is much more complex, dynamic, and balanced than they are at a human level, which we view as a binary equation. At any breathing moment in our lives, we have cells being bequeathed life and cells that are signaled to die. So even as we live, parts of us are constantly dying. In fact, if apoptosis were to not occur, an average human being would accumulate two tons of bone marrow over their life span and possess an intestine fifteen kilometers in length. Even at an individual cellular level, there is a constant dynamic push and pull between factors that favor apoptosis and factors that block it. Therefore, every cell within our body is dancing to forces that move it closer to or farther away from death, and in a broader sense, we comprise cells that are both coming alive and dying at all times simultaneously. What pushes us as humans closer to death is when the net pull of apoptotic forces exceeds that of mitotic ones.
The various ways cells die reveal insights into the life and culture of cells. Presumably cells do not feel or exhibit emotions or dwell on ethics or morality as human beings do. But the ecology and mechanisms of death among cells denote how truly linked life is to death. In fact, when a cell “forgets” how to die, it ends up becoming something that threatens to bring the entire organism down. Those are cells that cause cancer.
Defects in apoptosis are responsible for half of all cancers. Normal cells all have a sentinel guardian called tumor protein p53 (TP53). TP53 initiates apoptosis whenever it detects cell damage in normal cells, releasing agents to do its bidding called Puma, Noxa, and Bax, among others. In response to damage by radiation, toxins, or other factors, TP53 allows Puma, Noxa, and Bax to orchestrate a death so clean that it allows other cells to live in harmony. But in cancers such as chronic myeloid leukemia, owing to mutations in TP53, pro-life proteins such as BCL2 are more active, which prevents the body from adequately carrying out its cleansing operation, resulting in immortal cancer cells. The chemotherapy for chronic myeloid leukemia, imatinib, actually works by blocking proteins that are part of the BCL2 family. Other cancer drugs promote appropriate apoptosis in cancer cells by other mechanisms. Some do so by activating death receptors; others block survivin, a cellular protein that normally disables caspases. Death is, in fact, so important in cells that efforts to avert cell death, while keeping cells seemingly alive, saps their abilities, with survivors often referred to as “zombie cells.”12
Too much apoptosis, though, as one might imagine, is also not a good thing. In conditions such as Huntington’s, Parkinson’s, Alzheimer’s, or amyotrophic lateral sclerosis, toxic misfolded proteins accumulate in nerve cells, prematurely activating cell death. However, chemotherapeutic agents that enhance autophagy improve the ability of cells to eliminate these vile proteins. Excessive apoptosis occurs in diseases, such as stroke, heart attack, HIV/AIDS, and autoimmune conditions, and therefore experimental treatments are being developed to inhibit apoptosis intelligently in these conditions.
Insights into apoptosis have shed light on the social lives of cells. Death is not a solitary event, and rarely occurs without it being indicated. In a piece in Nature, Gerry Melino wrote, “Such social control of life and death are vital in complex multicellular networks,” and went on to ask, “Does social control inevitably imply navigation between conflicting signals?”13 The society of cells, free of individualism, functions only to preserve the multicellular organism—which is the cell’s home. Cells, as they age, are pegged, and acquiesce to a clean death. Our efforts at prolonging cell life often result in the cell surviving in a decrepit condition—referred to by Robert Horvitz in his Nobel lecture as “undead.”14 When I asked Dr. Horvitz what the existential and metaphysical implications were of our recently acquired understanding of how organisms actually die, he said, “Given the many years I’ve been studying cell death, it is perhaps surprising that only once before has someone approached me to discuss the existential questions that might relate what is known about cell death to human existence, including the issue of life and death.” To Dr. Horvitz, programmed death is more than just an accident and contains lessons that we can infer about how best to persist as a species. “Biology is sophisticated and evolution has selected sophisticated evolutionary solutions. Perhaps one could make an analogy and say that if we as a species are going to survive, we have to ensure that we do not irreparably do harm that would make such survival impossible.”
Many of the same tools that enact death are in fact extremely crucial for the life of not only the individual but the entire ecosystem. Falling leaves during autumn allow for renewal and constant reinvigoration of the trees that bore them. For the only thing worse than a cell that forgets how to live—is one that refuses to die.
* * *
AFTER IT BECAME clear that cells don’t die merely by happenstance, the next quest that scientists embarked on was to understand just how cells fall off the conveyor belt of life and are nominated to die. Was it all just a cosmic coincidence or was there something greater at play? Were all cells prisoners of fate and destiny or were their environment and actions responsible for their outcomes? Did cells exhibit age the same way multicellular organisms such as humans did? And was there a way we could have cells stave off the fatal handshake of death?
Now, while immortality is a theoretical construct, it is intriguing to ponder what prevents us from being able to achieve it. The first obvious answer is disease. While human beings debate the purpose of their existence ad nauseam, most biological organisms are geared for one purpose alone—living. Disease is simply any deviation from the carefully choreographed dance that achieves the basic functions of life. As our never-ending war on disease marches on, disease still represents the low-hanging fruit in our quest to extend life. For while diseases are discrete and recognizable detours from normalcy, there is something in the background, something as intrinsic as life itself, that constantly pegs us back: senescence.
Benjamin Gompertz, a British mathematician, realized in 1825 that there were two distinct drivers of human mortality.15 In addition to extrinsic events, such as injuries or diseases, there was an internal deterioration, which he called “the seeds of indisposition.” Manifesting as silvering hair, deepening voices, and retarding reflexes, aging is the most persistent of human foes. As tireless as waves striking the bluffs, as effective as the river that shaped the Grand Canyon, age continues to eat away at us even as we find better ways to prevent, cure, and manage disease.
Our current knowledge of the lives of cells began under somewhat unusual circumstances. Alexis Carrel was but a medical student in Lyon when he saw the president of France fatally stabbed by an anarchist.16 After the local surgeons’ sutures failed to hold together the president’s severed blood vessels, Carrel’s passion for sewing blood vessels was born and he engaged one of Lyon’s most deft embroiderers, Madame Leroudier, to teach him the art of suturing.17 Carrel translated what held together the most ornate dresses into techniques that revolutionized how human blood vessels and organs could be put back together. After he applied his newly acquired skills to achieve amazing clinical results, instead of being rewarded over the course of his career, Carrel was passed over multiple times for promotion by those envious of his brilliance. Further frustrations mounted, and he decided to jump ship and move to Canada to “forget medicine and to raise cattle beef.”18
Within months of his move to Canada, though, his talents were recognized and the University of Chicago recruited him. Over the next ten or so years, Carrel did more to advance surgery than almost any other surgeon during that time. A tribute in the Journal of the American Medical Association proclaimed some of his achievements: He “reunited vessels, inner lining to inner lining; he sutured artery to artery, vein to vein, artery to vein, and did this end to end, side to side, and side to end. He used patch grafts, autografts, homografts, rubber tubes, glass tubes, metal tubes, and absorbable magnesium tubes.… He transplanted the thyroid gland, spleen, ovaries, limbs, kidneys, and even a heart and so proved that, surgically, it was possible and easy to transplant organs.”19 Thus, much to the chagrin of detractors in his native France, Carrel was awarded the Nobel Prize in Medicine in 1912, the first to originate from the United States.
To Carrell, who had overcome so many challenges with his very hands, it seemed that nothing was beyond his reach. He had already repaired blood vessels thought previously irreparable and transplanted organs thought impossible to transplant. The natural progression of things led Carrel to study how to sustain human organs indefinitely—a necessary first step toward eradicating our mortal curse. Only recently had a way to culture cells outside the body been discovered, and Carrel was confident that the prevailing theory of cell division being finite—proposed by August Weismann, the previously mentioned discoverer of cell division—could be proven false.20
In his paper titled “On the permanent life of tissues outside of the organism,” published in the Journal of Experimental Medicine in 1912, he described experiments that would go on to constitute a “complete solution.”21 In his most famous experiments, Carrel removed hearts from chicken embryos, placed them on slides, and incubated those tissue fragments at a set temperature in a specific medium. He showed that the externalized heart tissue, unlike the normal chicken heart plagued by mortality, kept pulsating for many, many years and was presumed to be “permanent.”
According to Carrel, senility and death were preventable and resulted from “the accumulation of catabolic substances and exhaustion of the medium.” In effect, Carrel was saying that aging and death were due to external stimuli rather than to some internal predesigned mechanism. In the right setting, he claimed, cells and tissue could be freed from the evil humors they were imprisoned in, and in a world free of scarcity, life could be made permanent. Funded by the world’s then-richest man, John D. Rockefeller, and in conjunction with another man keen on redefining the human experience, Charles Lindbergh, Alexis Carrel kept his chicken heart pulsating for thirty-four years—even beyond his own death, maintained by his lab workers.22
Owing to Carrel’s experiments, eternal life appeared to be closer to attainment than it ever had been in the past, and in many ways, it hasn’t been closer since. But not everyone was fit for such drastic life extension. To Carrel, there were many not even fit for life to begin with. In his best-selling book, Man, the Unknown, he wrote that all criminals and those who have “misled the public in important matters, should be humanely and economically disposed of in small euthanasic institutions supplied with proper gases.”23 Women, in particular, were both unworthy and unequal. “The mothers abandon their children to the kindergarten in order to attend to their careers, their social ambitions, their sexual pleasures, their literary or artistic fancies, or simply to play bridge.”
However, the Second World War derailed his future plans. He went back to France to set up a hundred-bed field hospital. Unfortunately, his French hosts surrendered, and thereafter he operated the hospital during the Vichy government’s German-occupied rule and was assumed to be a collaborator. Even as he lived on war rations and operated this hospital, his health deteriorated, and he suffered two heart attacks before France was finally liberated. However, as soon as the Vichy government was overthrown, the new French government put him and his wife under house arrest. The American government tried to intervene, hoping to protect Carrel from what was seen to be an overaggressive reaction by the French. Yet before Carrel could be appropriately rehabilitated, he passed away, in November 1944 at the age of sixty-eight. Even though he died in his native land, he did so having been stripped of all titles in ignominy.
While eugenics died with him and in the defeat of Nazi Germany, Carrel had changed all prevailing thought about the life of cells. But his most enduring legacy would remain the sutures he had learned to sew so well from Madame Leroudier, as his advances in cell biology were unable to withstand the wear and tear of time.
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WHEN THE PROMINENT biologist Leonard Hayflick was born, in 1928, the chicken heart pulsating in Alexis Carrel’s lab was already sixteen years old and his ideas were widespread. Even when attempts to duplicate Carrel’s experiment failed, the investigators themselves assumed that this represented a failure of the culture the tissues grew in.24
Such doubts crossed Hayflick’s mind as well, as he was unable to get human embryonic cells to grow indefinitely in his cultures. In experiments he performed after completing his PhD at the University of Pennsylvania, he exposed human embryonic cells to extracts from cancer cells in the hope of inducing those cancerous changes in the human cells. However, he noted that after undergoing a specific number of divisions, the cells would stop proliferating. He wasn’t sure whether this was because there was some resource in the culture that was getting used up or because there was a buildup of toxic materials. Yet when he combined two populations of old male and younger female cells, the older cells would still die earlier, while the younger cells would continue to divide in the same medium until there were only female cells left. The male cells, in fact, died at the same rate as a separate control sample consisting only of male cells. In a subsequent experiment, Hayflick showed that cellular age was not related as much to time as it was to the number of DNA replications. He cryogenically froze a sample of cells, and after being rewarmed they still replicated the same number of times.25 This phenomenon was named “the Hayflick limit” by Australian Nobel laureate Macfarlane Burnet and proved once and for all that there was something innate in the cells that caused them to stop growing.26
Hayflick’s work helped to reverse a dogma that had been introduced into science by Alexis Carrel’s work since the early part of the twentieth century. While August Weismann had first theorized in 1889 that cell division was finite, Carrel’s chicken-heart experiment wiped that out of the scientific lexicon. Further investigation revealed that Carrel’s experiment was rigged and that he most likely knew that it was.27 Every time he added a feed to the culture, it would include new embryonic cells. Each chicken heart was continuously composed of newly added embryonic cells, as opposed to the cells he started with, which lasted for only a few months. But now that the Hayflick limit had become an established phenomenon, the real question was why such a limit existed. The answer to this question could provide the answer to why cells—and, by extension, humans—aged.
DNA, the tiny double-helixed code that underwrites our cells, clumps together to form chromosomes. Each human cell contains twenty-three pairs of chromosomes; sperm and ova contain twenty-three single chromosomes, and form twenty-three pairs when they join. After Hayflick’s discovery, scientists started to analyze the mechanisms underlying cell aging. When scientists first started to analyze cells to investigate the effect of aging, their attention was directed toward the very ends of the chromosomes.
Scientists noted that while central segments of chromosomes contained unique sequences of DNA that were similar across all cells within a species and were essential to program for the production of critical materials, the sequences at the ends of the chromosomes were quite curious. Firstly, the cell was unable to fully replicate the sequences at the end of the DNA strand.28 The strand lengths also differed within cells, unusual because DNA was otherwise extremely consistent.
Elizabeth Blackburn was barely thirty in 1978, when as part of her postdoctoral research at Yale University she published her findings regarding the terminal segments of the chromosomes in protozoa, a family of single-celled organisms that use hairlike extensions to move.29 What she found was very interesting: Unlike the rest of the chromosomes, which consisted of random sequences of DNA that could be used to print proteins and serve other cell functions, the terminal ends consisted of repeated sequences that were the same across species and served no specific programmatic purpose. The number of times the sequences were repeated varied from cell to cell30 and was also represented in human cells.31
Subsequent research showed not only that the length of these terminal segments, called telomeres, varied from cell to cell, but, importantly, that these telomeres appeared to get shorter with each cell division.32 These observations strongly suggested that telomeres were in fact responsible for the Hayflick limit after it was noted that when telomeres became very short, cells became unstable and apoptosis was induced.
In 1985, one of Elizabeth Blackburn’s students, Carol Greider, along with Blackburn, discovered telomerase, the enzyme that both synthesizes and elongates telomeres.33 By printing extra copies, telomerase can extend the length of telomeres in cells, and subsequent experiments showed that the addition of telomerase to otherwise normal cells could greatly extend their life span.34 In fact, a recent experiment has shown that if telomerase is reactivated in mice that have aged prematurely from having telomerase previously silenced, many of the manifestations of aging can be reversed.35 These terminal ends of chromosomes, which first caught the attention of scientists in the 1930s when it was noticed that the ends don’t participate in fusion events that occur between chromosomes, are now thought to hold the key to maintaining balance between life and death in cells.
Telomeres are a very visual representation, like tree rings, of the constant struggle for life. As telomeres get critically short, cells are unable to replicate any further without losing essential DNA material. The result is an instability that promotes cell damage and eventual demise. DNA damage is the hallmark of cell aging, and in addition to telomere shortening there are several other mechanisms that cause cells to age. Damage to mitochondria, the cell’s engines, results in the release of toxic materials that can hasten apoptosis.
Caloric and dietary restriction are now also known to promote longevity.36 Growth hormone and insulin growth factor, both responsible for growth in humans and many other organisms, have reduced activity as we age. However, purposefully down-regulating their activity by reducing dietary intake by about 20 to 40 percent puts organisms into survival mode. Sensing a reduced supply of nutrients, cells reduce their growth, metabolism, and replication, reducing the chance that errors will occur. This results in longer life spans. As we age, we also suffer from an exhaustion and depletion of stem cells, which otherwise provide a constant supply of fresh cells to join the ranks.
Cellular senescence appears to be as well regulated as every other aspect of cell life, making it clear that senescence is achieved and doesn’t merely happen. The reason cells age and are then replaced, like everything else in the microscopic world of cells, is to perpetuate life. While cells battle age, much as we do, with very robust repair mechanisms, they also recognize when cell damage begins to accumulate to a point of no return. It is at that point that cells weed out aging cells to protect the organism at large from uncontrolled death and necrosis. While telomerase, the enzyme that helps cells grow to perpetuity, may seem like a modern philosopher’s stone, it has a dark and twisted legacy. Far from being a purveyor of life, it is a harbinger of death and is found in nearly all immortal cancers.37 To remain in a state of never-ending growth, cancer cells use telomerase to constantly elongate their telomere segments, pushing death away and growing endlessly.
At a cellular level, immortality already has a name and a face: It’s called cancer, and it’s not particularly comely. The telomerase paradox—that telomerase is essential both for longevity and for sustaining malignant cells—is represented in many other attempts to prevent cellular demise. Our attempts to increase human life expectancy have had effects similar to those attempts at a cellular level and have changed the ecology and landscape of death in modern times. Our ongoing battle with aging, disease, and death has had profound effects on social and economic constructs.
Copyright © 2017 by Haider Warraich