The Song of the Cell: An Exploration of Medicine and the New Human

by Siddhartha Mukherjee

I switched off the microscope and thought about the strange temple of Shitala—and of how long and how hard it has been to cool or heat innate immunity to make it an agent of our medical needs.

Gin a body meet a body Comin thro’ the rye, Gin a body kiss a body— Need a body cry. —Robert Burns, “Comin Thro’ the Rye,” 1782

(India still reports eighty thousand snakebites a year, the largest number in the world.)

immunological memory.

Epistemic Good metaphor for toxic behavior

cell (T for thymus). But

Inner worlds, outer worlds, separated by membranes. What do T cells do during an infection? Imagine, as a human immune system might see it, that there are two pathological worlds of microbes. There is an “outer” world of a bacterium or a virus floating outside the cell, in lymph fluid or blood, or in tissues. And there is an “inner” world of a virus that is embedded and living within a cell. It is the latter world that presents a metaphysical, or rather a physical, problem. A cell, we said before, is a bounded, autonomous entity with a membrane that seals it from the outside. Its inside—the cytoplasm, the nucleus—is a closed sanctum, largely inscrutable from the outside, except for the signals, or receptors, that the cell chooses to send to its surface.

Antigen processing and presentation to CD4 and CD8 cells—the mainstays of T cell recognition—are slow but painstakingly methodical processes. Unlike an antibody, a gunslinging sheriff itching for a showdown with a gang of molecular criminals in the center of town, a T cell is the gumshoe detective going door to door to look for perpetrators hiding inside. In The Lives of a Cell, Lewis Thomas wrote: “Lymphocytes, like wasps, are genetically programmed for exploration, but each of them seems to be permitted a different solitary idea. They roam through the tissues, sensing and monitoring.” Unlike the B cell, though, the T cell isn’t looking for a culprit to come bursting out of the saloon, guns a-blazing. It is, like some omniscient Sherlock Holmes with a pipe and an umbrella, seeking the portent of a person. The debris left behind by an inner presence. A torn-up letter, with the fragment of a name, discarded in the trash can outside. (You might think of that crumpled piece of stationery, mounted within a trash can, as a peptide presented on an MHC molecule.)

We typically think of AIDS as a viral disease. But it is also equally a cellular disease. The CD4-positive T cell sits at the crossroads of cellular immunity. To call it a “helper” cell is to call Thomas Cromwell a mid-level bureaucrat; the CD4 cell is not so much a helper as it is the master machinator of the entire immune system, the coordinator, the central nexus through which virtually all immune information flows. Its functions are diverse. Its work begins, as we read before, when it detects peptides from pathogens, loaded on class II MHC molecules, and presented by cells. Then it jump-starts the immune response, activating it, sending alarms, enabling B cell maturation, and recruiting CD8 T cells to sites of viral infection. It secretes factors that enable cross talk between the various wings of the immune response. It is the central bridge between innate immunity and adaptive immunity—between all the cells of the immune system. The collapse of CD4 cells thus cascades rapidly into a collapse of the immune system in total.

Long before the birth of cell biology, Aristotle imagined the self as the core of being; a unity of the body and the soul. The physical boundary of the self, he proposed, was defined by the body and its anatomy. But the totality of the self was a unity of that physical vessel with a metaphysical entity that occupied it—the body filled by the soul. In principle, Aristotle, too, might have fretted about the possible invasion of the physical vessel by a foreign soul—indeed, “possession” was frequently used by psychics to explain mental and behavioral breakdowns—but he didn’t seem to sweat the question: once the physical vessel had been occupied by one soul, its potential invasion by—or fusion with—another soul didn’t bother him. In quite the opposite sense, some Vedic philosophers in India, writing between the fifth and second century BC, welcomed the erasure of the individual self and its fusion with the universal. They rejected the Greek dualism between the body and the soul—and, indeed, between an individual body and the cosmic soul. They termed the self atman. (There are many other Sanskrit words for the self besides atman, but it is the one that holds the most meaning.) The universal, multitudinous self, in contrast, was the Brahman. For these philosophers, the self was an ideal fusion of atman and Brahman, or perhaps more accurately, the seamless flow of the universal self through the individual self. However, this fusion/flow was reserved as a goal for spiritual attain...

In immunology, as with any science, there are moments of grand synthesis, when seemingly disparate observations and seemingly inexplicable phenomenon converge on a single mechanistic answer.

! Epistemic

They are under attack by themselves, because T cells that control other T cells, the policemen who police the police, are missing in action.

It is an unsolved quirk of the immune system that the cell type that confers active immunity and incites inflammation (the T cell) and the cell type that dampens these processes (the regulatory T cell) arise from the same parent cells: T cell precursors in the bone marrow. Indeed, aside from very subtle distinctions in genetic markers, T cells and T reg cells are anatomically indistinguishable. And yet they are functionally complimentary. Immunity and its opposite are twinned: the Cain of inflammation conjoined with the Abel of tolerance. Sometime in the future, we will understand why evolution chose to pair these cells. But the regulatory T cell remains a mystery—a cell that looks like it might activate immunity, but actually suppresses it.

Next was a man with systemic lupus erythematosus (SLE), often referred to simply as lupus. The illness is named after a wolf, either because Roman physicians thought that the skin lesions of this form of horror autotoxicus reminded them of wolf bites or, more likely, because the rash that spreads across the face, crossing the bridge of the nose and under the eyes, was reminiscent of a wolf’s markings.

Into the notable city of Florence, fair over every other of Italy, there came the death-dealing pestilence, which… had some years before appeared in the parts of the East and… had now unhappily spread toward the West… To the cure of these maladies nor counsel of physician nor virtue of any medicine appeared to avail or profit aught… The mere touching of the clothes or of whatsoever other thing had been touched or used of the sick appeared of itself to communicate the malady to the toucher… Each thought to secure immunity for himself. Some… lived removed from every other and shut themselves up in those houses where none had been sick and where living was best. —Giovanni Boccaccio, The Decameron

We were stepping, it seemed, quite confidently from basic immunology to applied immunology. And then, biblically, we tumbled. On January 19, 2020, a thirtysomething man, just off a flight from Wuhan, China, walked into a clinic in Snohomish County, Washington, with a cough. To read that first case report, published in the New England Journal of Medicine in March that year, is to experience an ascending chill: “On checking into the clinic, the patient put on a mask in the waiting room.” Who stood next to him in that room? How many people had he infected in the past days? Who was sitting across the aisle on the flight from Wuhan to Seattle? “After waiting approximately twenty minutes, he was taken into an examination room and evaluated.” Was the doctor who examined him masked? The nurse who checked his temperature? Where are they now? “He disclosed that he had returned to Washington State on January 15 after traveling to visit family in Wuhan, China.” On January 20, a nasal swab and an oral swab (and subsequently, stool samples) were sent to the Centers for Disease Control and Prevention. Both tested positive for a novel coronavirus: SARS-COV2. On the ninth day of his illness—and the fifth day of hospitalization—his condition deteriorated. His oxygen levels dropped to 90 percent—decidedly abnormal for a young man with no prior lung condition. A chest X-ray revealed hazy, opaque streaks across his lung, signaling a deepening pneumonia. His liver function blood tests revealed ...

More than two years have passed since the man with a cough walked into the Seattle clinic. As I write this, in March 2022, the world has recorded nearly 450 million infections, nearly 6 million deaths (both numbers are likely vast underestimates, given the lack of reliable reporting of testing and deaths from the virus). The contagion has leapt across the globe, leaving virtually no corner untouched. Waves of viral strains bearing new mutations have appeared, some more lethal than others—Alpha, Delta, and now, Omicron. More than sixty vaccines against the virus are undergoing clinical tests. Three have been approved in the United States, nine approved by the World Health Organization (WHO), and several others are still in development. Wealthy nations, with mature health care and delivery systems, have been brought to their knees. The United Kingdom has had more than 160,000 deaths. In the United States, the official number of deaths is 965,000. And the counts of the dead, the sick, the ravaged, the displaced, the bankrupted, the bereaved goes on. And on. I cannot shake the images, or the sounds, of the pandemic. Who can? The orange body bags, piled in bunks, in makeshift morgues. The mass graves in Ecuador. The constant wailing of ambulance sirens outside my hospital, fusing together until all I could hear was a wall of shrieks; the Emergency Room, in the spring of 2021, packed to its brim, with stretchers spilling into the corridors; the patients gasping as they drowned i...

I think, sometimes, of a legend. Bali, a demon king, has conquered three worlds—the earth, the underworld, and the heavens. A tiny man with smoky eyes and an umbrella, Vamana—Vishnu’s avatar—appears before him and asks him to grant him a single wish. His arrogance inflated into munificence, Bali, the demon king, agrees. Vamana asks for something ludicrously small: a square plot of land whose edges are defined by the distance that he might cover in three strides. The man is—what—two arm lengths tall? He wants a few square feet of a kingdom that stretches to infinity? Bali laughs it off; yes, of course, the little man can have his little plot of land. And then, as Bali watches in terror, Vamana expands. His body arches exponentially through the skies. His first step crosses the entire Earth. His second stretches across the heavens; the third arcs over the netherworld. There is no more kingdom to grant. He plants his foot on Bali’s head and pushes him into the lower reaches of hell. The analogy fails quite obviously in some parts—Vamana was a divine being, and the virus was anything but a divine intervention. Our failings, unfortunately, were all too human: a fraying, sclerotic global public health system, the absence of preparedness, misinformation that spread, virus-like, through nations, supply chain issues that made it impossible to procure protective masks and disposable medical suits, strong-men leaders of nations who turned out to be flaccid in their responses to the v...

Science hunts for truths. There’s a haunting image in one of Zadie Smith’s essays that involves a cartoon of Charles Dickens surrounded by all the characters that he’s invented: tubby Mr. Pickwick in an ill-fitting waistcoat, adventurous David Copperfield in a top hat, bedraggled and innocent Little Nell. Smith is writing about authors—in particular, about the out-of-body, in-another-mind experience that a fiction writer feels when she fully inhabits the mind, body, and world of a character that she’s created. That familiarity, or intimacy, feels like a “truth.” “Dickens didn’t look worried or ashamed,” Smith writes of the cartoon. “Didn’t appear to suspect he might be schizophrenic or in some other way pathological. He had a name for his condition: novelist.” Imagine another character now, except surrounded by half-ghosts. Some of these “characters”—like type I interferon, the toll-like receptor, or the neutrophil—are mostly visible, except they exist in the half-light of visibility. We think we know and understand them, but we don’t, really. Some only cast shadows. Some are completely invisible. Some mislead us about their identities. And there are others around us whose presence we cannot even sense. We haven’t even met them, or named them, yet. I, too, have a name for this condition: scientist. We look, we create, we imagine—but find only incomplete explanations for phenomena, even phenomena we may have (partially) discovered through our own work. We cannot inhabit the...

triumphalism fails in the face of more than six million deaths. The pandemic energized immunology, but it also exposed gaping fissures in our understanding. It provided a necessary dose of humility. I cannot think of a scientific moment that has revealed such deep and fundamental shortcomings in our knowledge of the biology of a system that we had thought we knew. We have learned so much. We have so much left to learn.

What I felt wasn’t writer’s block, but writer’s languish: I wrote, yes, but everything that I put on the page seemed to lack life and energy. What preoccupied me was the collapse of infrastructure, and of homeostasis, that we had witnessed during the worst of the crisis in the United States, and then, around the world. When my frustration reached its crest, I near-regurgitated an essay, later published in the New Yorker. It was part cri de coeur, part plea for change, part autopsy of what I had witnessed in the middle of the pandemic. Medicine, I wrote, isn’t a doctor with a black bag. It’s a complex web of systems and processes. And systems that we had thought were self-regulating and self-correcting, like a human body in good health, turned out to be exquisitely sensitive to turbulence, like the body during critical illness.

In 1628, Harvey published his conclusions in a seven-volume series now typically referred to as De Motu Cordis (An Anatomical Account of the Motion of the Heart and Blood) that would upset the very foundations of anatomy and physiology of the heart. The heart, Harvey argued, was a pump that moved blood circuitously through the body—from arteries to veins and back again. These views, he wrote, “pleased some more, others less: some […] calumniated me and laid it to me a crime that I had dared to depart from the precepts and opinions of all anatomists: others desired further explanation of the novelties which they said were both worthy of consideration, and might perchance be found of signal use.”

I. There are three fundamental kinds of muscle cells in the human body: cardiac muscle, which constitutes the main subject of this chapter; skeletal muscle (the kind that moves your arms on command); and smooth muscle (the kind that moves involuntarily, but consistently, allowing, say, liquid in the intestines to keep moving). All three muscles use variants of the actin/myosin system, along with a smattering of other proteins, for contractility.

For several decades in the late nineteenth century, the most versatile and mystifying of cells in the body was not even considered a cell. In fact, it was not visible to most microscopists: the structure of a neuron was largely hidden. In 1873, Camillo Golgi, the Italian biologist working in Pavia, found that if he added a solution of silver nitrate to a slice of translucent neuronal tissue, a chemical reaction occurred, resulting in a black stain that accumulated within some of the neurons. Under the microscope, Golgi saw a lacy network. He thought that the network represented a continuous connection—a “reticulation,” as he called it. Cell theory was itself in its infancy—Schwann and Schleiden had proposed that all organisms were collections of cells in 1838 and 1839—and so, Golgi wondered whether the entire nervous system was a spiderweb of “cellular appendages,” an “inextricable tangle” of interconnected, contiguous cellular extensions, as one writer called it. It was a mumbo-jumbo theory: as Golgi imagined it, the whole nervous system was like a fishnet, composed of wiry extensions sent out by the brain.

A rebellious young pathologist from Spain challenged Golgi’s theory. A gymnast, an athlete, and an avid draftsman—“shy, unsociable, secretive, brusque,” as one biographer described him—Santiago Ramón y Cajal was the son of an anatomy teacher who, in the tradition of Vesalius, took his young boy to the graveyards in his town to dissect specimens. As a child, Cajal was known for his elaborate pranks. His first “book” was on the construction of slingshots—a fusion, as it were, of his love for accuracy and his disdain for authority. He also drew compulsively—bird’s eggs, nests, leaves, bones, biological specimens, anatomical structures: all forms of natural objects fascinated him, and he sketched them in his notebook. He would later call this drawing habit his “irresistible mania.” Cajal attended medical school in Zaragosa and eventually moved to Valencia, where he was appointed as a teacher of anatomy and pathology. In Madrid, he chanced upon a friend who had just returned from Paris where he had learned Golgi’s staining method.

In 1906, Cajal and Golgi were jointly awarded the Nobel Prize for their elucidation of the structure of the nervous system. It might have been the oddest prize in its history because it was an armistice more than an award: Cajal’s and Golgi’s ideas about the structure of the nervous system were precisely opposed to each other. In time, with the invention of more powerful microscopes, Cajal’s theory—of discrete neurons communicating with each other, and the impulse moving from cell to cell in a directional course—would be proved right. The nervous system was made of wires and circuits, but the “wires” were not a contiguous reticulum, but rather individual cells that had the capacity to collect information and transmit it to another series of neurons.

saw the arrival of a small electrical impulse—a mini wave—followed by a large wave of charged ions moving into the neuron. The large wave subsided, and dipped, and then the system was reset to normal. Again and again, when they stimulated the axon, they saw the same rising spike of charge, and its restoration to normal. They had observed the dynamics of a nerve conducting its signal to another nerve. The war interrupted Hodgkin and Huxley’s collaboration for nearly seven years. Hodgkin, the engineer-tinker, was sent off to make oxygen masks and radars for pilots; Huxley, the mathematician, was deployed to use equations to make machine guns more accurate. In 1945, shortly after the war ended, they resumed their work in Plymouth, scouring the catch for squid and delving deeper and deeper into the nervous system, finding more accurate ways to measure the flow of charge into the neuron, culminating in a mathematical model to describe the movement of ions into the neuronal cell. Nearly seven decades later, neuroscientists are still using the Hodgkin and Huxley equations, and their experimental methods, to understand the nervous system. The broad outlines of how a neuron “chatters” are now understood. Perhaps we can turn to one of Cajal’s drawings as a template to elucidate the movement of a signal through a nerve. Imagine the nerve, first, in its “resting” state. At rest, the internal milieu of the neuron contains a high concentration of potassium ions and a minimal concentrati...

takes a courageous person,” the poet Kay Ryan once wrote, “to leave spaces empty”—and Cajal, the draftsman-scientist, was anything but timorous. That space—about twenty to forty nanometers in distance—is left blank. It is tiny; you could wave it away. Perhaps it’s an artifact of microscopy or staining. But like the negative space in a Chinese painting, that space might represent the most important element of the whole drawing—and arguably, of the entire physiology of the nervous system. It immediately raises the question of why such a blank space exists: If you were building a nervous system as a box of wires, then what foolish electrician would leave gaps between wires? But Cajal drew exactly what he saw—the horse of observation leading the cart of theory. And yet again, as with so much in this history, it was seeing that led to unbelieving.

It might be useful to distinguish two broad kinds of problems in science. The first kind—call it the “eye in the sandstorm” problem—arises when there’s such immense confusion in a field that no pattern or road map is visible. There’s sand in the air everywhere you look, and a completely new pathway of thinking is needed. Quantum theory serves as a good example. In the early 1900s, as the atomic and subatomic worlds were discovered, the heuristic principles of Newtonian physics just would not suffice, and a shifted paradigm about this atomic/subatomic world was required to get out of the sandstorm.

One chattering, thoughtful neuron has “spoken” to the next. The neuron’s two countermelodies are woven together in tandem, like a child’s chant: electrical, chemical, electrical, chemical, electrical.

The reasons for this paring back of synapses is a mystery, but synaptic pruning is thought to sharpen and reinforce the “correct” synapses, while removing the weak and unnecessary ones. “It reinforces an old intuition,” a psychiatrist in Boston told me. “The secret of learning is the systematic elimination of excess. We grow, mostly, by dying.” We are hardwired not to be hardwired, and this anatomical plasticity may be the key to the plasticity of our minds. But who does the pruning of synapses? In the winter of 2004, Beth Stevens joined the laboratory of Ben Barres, a neuroscientist at Stanford. “When I began my work in Ben’s lab, little was known about how specific synapses are eliminated,” she told me. Stevens and Barres focused their attention on visual neurons: the eye would be the eye to the brain. In 2007, they announced a startling discovery. Stevens and Barres found that glial cells were responsible for this pruning of synaptic connections in the visual system. The work, published in Cell, garnered enormous attention, but also threw open a host of new questions. Which specific glial cell was responsible for the pruning? And what was the mechanism of pruning? The following year, Stevens moved to Boston Children’s Hospital, to set up her own lab. When I visited her on an icy March morning in 2015, the lab was thrumming. Graduate students were folded over microscopes. One woman sat on her bench determinedly mashing a freshly biopsied fragment of a human brain into in...

In the spring of 2017, I was overwhelmed by the most profound wave of depression that I have ever experienced. I use the word wave deliberately: when it finally burst on me, having crept up slowly for months, I felt as if I were drowning in a tide of sadness that I could not swim past or through. Superficially, my life seemed perfectly in control—but inside, I felt drenched in grief. There were days when getting out of bed, or even retrieving the newspaper outside the door, seemed unfathomably difficult. Simple moments of pleasure—my child’s funny drawing of a shark, or a perfect mushroom soup—seemed locked away in boxes, with all their keys thrown into the depths of the ocean. Why? I could not tell. Part of it, perhaps, was coming to terms with my father’s death a year before. In the wake of his passing, I had thrown myself manically back to work, neglecting to give myself time and space to grieve. Some of it was confronting the inevitability of aging. I was at the edge of the last years of my forties, staring into what seemed like an abyss. My knees hurt and creaked when I ran. An abdominal hernia appeared out of nowhere. The poems that I could recite from memory? I would now have to search my brain for words that had gone missing (“I heard a Fly buzz—when I died— / The Stillness in my Room / Was like”… um… like… like what?). I was becoming fragmented. I was officially entering middle age. It wasn’t my skin that began to sag, but my brain. I heard a fly buzz. Things got ...

His Bernese mountain dog, Alpha, lumbered, drooling, by our side.

I was reminded of the Carl Sandburg poem: “The fog comes / on little cat feet. / It sits looking / over harbor and city / on silent haunches / and then moves on.” My brain felt perpetually fogged, as if some creature had descended on slow, silent haunches, but would not move on. Andrew Solomon, the writer, once described depression as a “flaw in love.” But in medical terms, it was a problem with the regulation of neurotransmitters and their signals. A flaw in chemicals. “Which chemicals? What signals?” I asked Paul. I knew that serotonin, the neurotransmitter, had something to do with it.

There isn’t enough serotonin in the synapse, and so the electrical circuits that respond to the chemical don’t get enough stimulation. The inadequate stimulation of mood-regulating neurons results in depression.

discovered a “slow” pathway, instigated by serotonin, that might be responsible for depression. Serotonin, Greengard and other researchers had found, doesn’t only act as a “fast” neurotransmitter, and depression isn’t just a malfunctioning neuronal circuit that can be reset by increasing serotonin in the synapse. Rather, serotonin sets off a “slow” signal in neurons—biochemical signals that come on cat’s feet—including altering the activity and function of several intracellular proteins that Greengard’s lab had identified. Paul believes that these proteins, which modify neuronal activity, are crucial to the slow signaling in neurons that regulate mood and emotional homeostasis. In his earlier work, he had shown that one such factor, called DARPP-32, is critically responsible to the way a neuron responds to another transmitter, called dopamine, which is involved in many other neurological functions, including our mind’s response to reward and addiction. “It’s not just the level of serotonin,” Paul said emphatically, jabbing his fingers in the air. The New York air was clear and bitingly cold, and his breath left a drifting trail of mist behind him. “That’s way too simple. It’s what serotonin does to the neuron. The way it changes the neuron’s chemistry, and its metabolism,” he said. “And that might vary from one individual to the next.” He turned to face me. “In your case, there might be inputs, or genetic reasons, that makes the response more difficult to sustain or restore.”

Depression is a flaw in love. But more fundamentally, perhaps, it is also a flaw in how neurons respond—slowly—to neurotransmitters. It is not just a wiring problem, Greengard believes, but rather a cellular disorder—of a signal, instigated by neurotransmitters, that somehow malfunctions and creates a dysfunctional state in a neuron. It is a flaw in our cells that becomes a flaw in love.

Epistemic depression mental health and brain 🧠 chemistry neuron serotonin

“Like many patients that I’ve seen before and after her, her metaphors for her illness were vertical. She was trapped inside a hole, a void. She had fallen into it. Others would talk about caves; about force fields that pushed them down into something. I hadn’t realized it then, but listening to the metaphors was absolutely vital. It was the metaphors that allowed me to track whether a patient was responding or not.” To position the electrode accurately into BA25, the neurosurgeon collaborating with Mayberg, Andres Lozano, had to put a frame around the patient’s head (the frame acts like a three-dimensional GPS system to track the electrode’s position as the surgeon introduces it into the brain). As Mayberg tightened the clasps of the stereotactic frame, the patient looked at her blankly, registering neither fear nor apprehension. “Here she was, a woman about to have holes bored into her head and a totally untested procedure performed in her brain, and all she could register was numbness. Nothing. That’s when I knew how bad it was for her.”

let’s not speak any language, let’s stop for one second, and not move our arms so much. —Pablo Neruda, “Keeping Still”

Type 1 diabetes, which affects several million patients around the globe, is a disease in which immune cells attack the beta-islet cells of the pancreas. Without insulin, the body cannot sense the presence of sugar—even if there is enough of the chemical in the blood. The cells in the body, imagining that the body has no sugar, begin to scramble around for other forms of fuel. The sugar, meanwhile, all readied up but with nowhere to go, spikes threateningly in the blood, and spills into the urine. Sugar, sugar everywhere—but not a molecule in cells to satiate them. It is one of the defining metabolic crises of the human body—cellular starvation in the presence of plenty. For decades since the discovery of insulin, the lives of millions of type 1 diabetics have been transformed.

Every human begins his or her life as a single pluripotent cell

!

You go out for dinner one evening. Perhaps in Venice, Italy—a resplendent restaurant near the Giardini, the public gardens of the city near the banks of the Bacino di San Marco. You begin with baccala manticato, the whipped salt-cod concoction that the Venetians stole from the Portuguese and appropriated into a national culinary monument. There’s a mound of toasted bread and a gigantic bowl of rigatoni to follow, and enough Chablis to fill a small canal. Perhaps you don’t realize as you walk back that a cellular cascade has been activated. Leave aside digestion for a moment. It is the metabolic cascade—and the restoration of chemical balance—that is the small miracle of cell biology that unfolds in your body as you walk back to your hotel. The carbohydrates from the bread and rigatoni are digested into sugars—ultimately, into glucose. The glucose is picked up from the intestines, absorbed into blood and moved into circulation. When the blood reaches the pancreas, it senses the spike in glucose, and sends out insulin. The insulin, in turn, moves the sugar from the blood into all the cells of your body, where it can be stored, if needed, or used for energy, as needed. The brain is the ultimate recipient of these signals: if the sugar drops too low, it reacts by sending out converse signals. Yet other hormones, secreted by different cells, send signals to release stored sugars into the blood. The stores come from liver cells, which respond, at least transiently, by releasing ...

In the early spring of 2020, the labs were closed because of Covid metastasizing through New York and the world. I was seeing limited numbers of patients in the hospital—partly because, yet unvaccinated (the vaccines were yet to be approved), I feared transmitting an infection to my chemotherapy-receiving patients whose immune systems could not battle a lethal virus. I still tended to the sickest, the most vulnerable. The oncology wing of the hospital went on heroically, kept alive by nurses. When not in the hospital or the lab, I spent my weekends in a house on a bluff that overlooked Long Island Sound. By the early light of morning, with the geometric crosshatches of sunbeams streaming across the lawn like rays of light coming out a prism, I would watch two ospreys that had come to nest there. They would fly up above the ocean, and then, miraculously, seem to sit still in midair—even while capricious gusts of wind might arrive from any direction. The writer Carl Zimmer described the same phenomenon in bats. Their miraculous fixity in midair, he wrote, was another form of homeostasis at work. The liver, pancreas, brain, and kidney are four of the principal organs of homeostasis.II The pancreatic beta cells control metabolic homeostasis through the hormone insulin. The kidneys’ nephrons control salt and water, maintaining a constant level of salinity in the blood. The liver, among many of its functions, prevents us from being soused in toxic products, including ethanol. Th...

Old age is a massacre,” Philip Roth wrote. But in truth it is a maceration—the steady grind of injury upon injury, the unstoppable decline of function into dysfunction, and the inexorable loss of resilience. Humans counter this decline by two overlapping processes—repair and rejuvenation. By “repair,” I am referring to the cellular cascade that begins upon injury. It is typically marked by inflammation, followed by the growth of cells to seal the damage. “Rejuvenation,” on the other hand, refers to the constant replenishment of cells, typically from a reservoir of stem or progenitor cells, in response to the natural death and decay of cells. Both diminish—either in the number of stem cells or in their function—drastically with age. The rate of repair decelerates. The reservoir of rejuvenation decays.

“He not busy being born is busy dying” […] You are busy being born the whole first long ascent of life, and then, after some apex, you are busy dying: that’s the logic of the line. —Rachel Kushner, The Hard Crowd

On August 6, 1945, at about eight fifteen in the morning, thirty-one-thousand feet above the Japanese city of Hiroshima, an atomic bomb nicknamed Little Boy was dropped from an American military aircraft, a B-29 bomber nicknamed the Enola Gay. The bomb took about forty-five seconds to descend, and then detonated in midair, nineteen hundred feet above the Shima Surgical Hospital, where nurses and doctors were at work, and patients still in their beds. It released about the energetic equivalent of fifteen kilotons of TNT—about thirty-five thousand car bombs going off at once. A circle of fire, more than four miles in radius, spread out from the epicenter, destroying everything in its wake. The tar on the streets boiled. Glass flowed like liquid. Houses were flicked into oblivion, as if by a giant, incinerating hand. Outside the stone steps of Sumitomo bank, a man or woman who was vaporized instantly left a shadow of herself on the stone that had been blistered white by the conflagration. The waves of death that followed had three crests. About seventy thousand to eighty thousand people—nearly 30 percent of the city’s population—were broiled to death almost instantly. “I was trying to describe the mushroom [cloud], this turbulent mass,” one of the tail gunners of the aircraft wrote: “I saw fires springing up in different places, like flames shooting up on a bed of coals […] it looked like lava or molasses covering the whole city, and it seemed to flow outward into the foothil...

Read this with Jude

In 1896, the biologist Edmund Wilson used the phrase “stem cell” to describe a cell capable of differentiation and self-renewal, just as Hacker had observed in Cyclops.

backgrounds. McCulloch—stout, short, hefty—was the scion of an “Old Money Toronto” family, as one biographer described it. He had a lively, wandering intellect: “[h]e thought tangentially, often playing connect the dots.” McCulloch trained in internal medicine at the Toronto General Hospital. He was recruited, briefly, as the head of hematology at the Ontario Cancer Institute in 1957 but found himself bored with the humdrum practice of medicine and soon left to become a full-time researcher. Till, in contrast, was a tall, skinny farmhand from Saskatchewan with a PhD from Yale in biophysics. He had an arrow-like mind, was mathematically inclined, and relentless about details. To McCulloch’s inventive madness, he brought method. There was complementarity, too, in their interests and expertise. Till had trained in radiation physics; he knew how to calibrate radiation and measure its effects on the body (he had been a student of the notoriously exacting Harold Johns, who had worked on the effects of cobalt radiation). McCulloch was a hematologist, with an interest in blood

Tenderness and rot share a border. And rot is an aggressive neighbor whose iridescence keeps creeping over. —Kay Ryan, 2007

In cell biological terms, then, it might be easier to imagine injury, or aging, for that matter, more abstractly, as a furious battle between a rate of decay and a rate of repair, with each rate unique for every individual cell, and individual organ. In some organs, injury overwhelms repair. In some organs, repair keeps apace with injury. In yet other organs, there’s a delicate equilibrium between one rate and another. The body, in its steady state, seems to be maintained—suspended—in constancy. Don’t just do something, stand there. But standing there, standing still, is not a statis but a frenetically active process. What appears as “stillness”—stasis—is, in fact, a dynamic war between these two competing rates. “At death you break up,” Philip Larkin wrote, “the bits that were you / Start speeding away from each other for ever / With no one to see.” But death isn’t a flying apart of organs. It is the withering grind of injury set against the ecstasy of healing. Tenderness, as Ryan puts it, combatting rot. The central corporals in this pitched battle are cells—cells dying in tissues and organs, and cells regenerating tissues and organs. Return, for a moment, to the notion of homeostasis—the maintenance of a constancy in the internal milieu. We first evoked this idea to understand how the cell maintains its internal fixity. We then used it to understand how a healthy body adjusts to metabolic and environmental changes—salt load, waste disposal, sugar metabolism. We apply it...

Mortal Epistemic

I do not know which to prefer, The beauty of inflections Or the beauty of innuendoes, The blackbird whistling Or just after. —Wallace Stevens, “Thirteen Ways of Looking at a Blackbird”