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

by Siddhartha Mukherjee

My purpose is not to write a comprehensive history of medicine or of the birth of cell biology. Roy Porter’s The Greatest Benefit to Mankind: A Medical History of Humanity, Henry Harris’s The Birth of the Cell, and Laura Otis’s Müller’s Lab are exemplary accounts. This, rather, is the story of how the concept of the cell, and our comprehension of cellular physiology, altered medicine, science, biology, social structures, and culture. It culminates in the vision of a future in which we learn to manipulate these units into new forms, or perhaps even create synthetic versions of cells, and parts of humans.

cancer cells don’t “invent” any of these properties. They don’t build anew, they hijack—or, more accurately, the cells that are fittest for survival, growth, and metasisis are naturally selected. The genes and proteins that cells use to generate the building blocks required for growth are appropriated from the genes and proteins that a developing embryo uses to fuel its fierce burst of expansion during the first days of life. The pathways used by the cancer cell to move across vast bodily spaces are commandeered from those that allow inherently mobile cells in the body to move. The genes that enable unfettered cell division are distorted, mutated versions of genes that allow cell division in normal cells. Cancer, in short, is cell biology visualized in a pathological mirror.

What will the future bring? Let me clarify: I use the phrase “new human” throughout the book, and in its title. I mean it in a very precise sense. I explicitly do not mean the “new human” found in sci-fi visions of the future: an AI-augmented, robotically enhanced, infrared-equipped, blue-pill-swallowing creature who blissfully cohabitates the real and virtual worlds: Keanu Reeves in a black muumuu. Nor do I mean “transhuman,” endowed with augmented abilities and capacities that transcend the ones we currently possess. I mean a human rebuilt anew with modified cells who looks and feels (mostly) like you and me. A woman with crippling, recalcitrant depression whose nerve cells (neurons) are being stimulated with electrodes. A young boy undergoing an experimental bone marrow transplant using gene-edited cells to cure sickle cell disease. A type 1 diabetic infused with his own stem cells that have been engineered to produce the hormone insulin to maintain a normal blood level of glucose, the body’s fuel. An octogenarian who, following multiple heart attacks, is injected with a virus that will home to his liver and permanently lower artery-clogging cholesterol, thus reducing his risk of another cardiac event. I mean my father, implanted with neurons, or a neuron-stimulating device, that would have steadied his gait so that he might not have suffered the fall that led to his death. I find these “new humans”—and the cellular technologies used to create them—vastly more exciting ...

True knowledge is to be aware of one’s ignorance. —Rudolf Virchow, letter to his father, ca. 1830s

Theories of vitalism had existed since Aristotle’s time, but the fusion of vitalism with late-eighteenth-century Romanticism produced an ecstatic depiction of Nature suffused with a special “organic” animus that was irreducible to any chemical or physical matter or force. French histologist Marie-François-Xavier Bichat in the 1790s and German physiologist Justus von Liebig in the early 1800s were both influential proponents. In 1795, the movement found its richest poetic voice in Samuel Taylor Coleridge, who imagined all of “animated nature” trembling into existence as this vital force flowed through it, just as a breeze might resonate through a harp and produce music that is irreducible to its mere notes. As Coleridge wrote: “And what if all of animated nature / Be but organic Harps diversely framed / That tremble into thought, as o’er them sweeps / Plastic and vast, one intellectual breeze / At once the Soul of each, and God of all.”

It's basically pseudoscience saying that souls exist.

The final phase of Rudolf Virchow’s life bore testimony not only to his theories about the cooperative social organization of the body—cells working with cells—but also a belief in the cooperative social organization of the state: humans working with humans. Immersed within a society that was becoming progressively racist and anti-Semitic, he argued vehemently for equality among citizens. Illness was an equalizer; medicine was not designed to discriminate. “Admission to a hospital must be open to every ill person who stands in need of it,” he wrote, “whether he has money or not, whether he is Jewish or heathen.”

In 1859, he was elected to the Berlin City Council (and eventually, in the 1880s, to the Reichstag). And he began to witness in Germany the resurgence of a malignant form of radical nationalism that would eventually culminate in the Nazi state. The central myth of what would later be termed “Aryan” racial superiority, and a nation dominated by “clean” Volk who were blond, blue eyed, and white skinned, was a pathology already sweeping malevolently through the country. Virchow’s response, characteristically, was to reject accepted wisdom and to try to restrain the surging myth of racial division: in 1876, he began to coordinate a study of 6.76 million Germans to determine their hair color and skin tone. The results belied the mythology of the state. Only one in three Germans bore the hallmarks of Aryan superiority, while more than half was a mixture: some permutation of brown or white skinned, or blond or brown haired and blue eyed or brown eyed. Notably, 47 percent of Jewish children possessed a similar permutation of features, and a full 11 percent of Jewish children were blond and blue eyed—indistinguishable from the Aryan ideal. He published the data in the Archive of Pathology in 1886, three years before the birth of an Austrian-born German demagogue who would prove to be a master of myth building and would succeed, despite scientific data, to create races out of faces and utterly destroy the ideas of civility that Virchow had so radically advanced.

what was the association between putrefaction caused by microbial cells and human disease? The first hint of a potential link came from a Hungarian obstetrician, Ignaz Semmelweis, who worked as an assistant in a Viennese maternity hospital in the late 1840s. The clinic was divided into two wards: the first clinic and the second clinic. Childbirth, in the nineteenth century, was almost as much life threatening as it was life giving. Infections—puerperal fever, or, more colloquially, “childbed fever”—caused postpartum death rates that ranged from 5 percent to 10 percent for mothers. Semmelweis noted a peculiar pattern: compared with the second clinic, the first clinic had a significantly higher rate of maternal mortality from childbed fever. News of this discrepancy, spread via gossip and rumor throughout Vienna, was an open secret. Pregnant women would beg, cajole, or manipulate their way to be admitted to the second clinic. Some women, wisely, even opted for so-called street births—outside the clinics—reasoning that the first clinic was a far more dangerous place to have a baby than the street.

Under the circumstances, I can hardly blame the women.

“What protected those who delivered outside the clinic from these destructive unknown endemic influences?” Semmelweis mused. It was a rare opportunity to perform a “natural” experiment: two women, with the same condition, entered through two doors of the same hospital. One emerged with a healthy newborn; the other was dispatched to the morgue. Why? Like a detective eliminating potential culprits, Semmelweis made a mental list of causes, crossing them off one by one. It wasn’t overcrowding, or the women’s ages, or the lack of ventilation, or the length of their labor, or how close the beds were to one another. In 1847, Semmelweis’s colleague Dr. Jacob Kolletschka cut himself with a scalpel while performing an autopsy. He was soon febrile and septic; Semmelweis could hardly help but notice that Kolletschka’s symptoms mirrored those of the women with childbed fever. Here, then, was a potential answer: the first clinic was run by surgeons and medical students who shuttled casually between the pathology department and the maternity ward—from performing cadaver dissections and autopsies straight to delivering babies. In contrast, the second clinic was run by midwives, who had no contact with cadavers and never performed autopsies. Semmelweis wondered if the students and surgeons, who routinely examined women without gloves, were transferring some material substance—“cadaverous material,” he called it—from the decomposing cadavers into a pregnant woman’s body. He insisted that th...

As amazing as this is, it ruined his career.

As stunning as the results were, Semmelweis had no explanation that he could visualize. Was it blood? A fluid? A particle? Senior surgeons in Vienna didn’t believe in germ theory and had no interest in a junior assistant’s insistence that they wash their hands between the clinics. Semmelweis was harassed and ridiculed, passed over for a promotion, and eventually dismissed from the hospital. The idea that childbed fever was, in fact, a “doctor’s plague”—an iatrogenic, physician-induced disease—could hardly sit well with the professors of Vienna. He wrote increasingly frustrated and accusatory letters to obstetricians and surgeons all over Europe, all of whom dismissed Semmelweis as a crank. He eventually packed off to the backwaters of Budapest, only to suffer a mental breakdown. He was admitted to an asylum where the guards beat him, leaving him with broken bones and a gangrenous foot. Ignaz Semmelweis died in 1865, most likely of sepsis caused by the injuries; consumed, possibly, by germs—the very “material” substance that he had tried to identify as a cause of infections.

Sad end to a man who did a lot for science 😔

Bacteria are disturbingly, ferociously, uncannily successful. They dominate the cellular world. We think of them as pathogens—bartonella, pneumococcus, salmonella—because a few of them cause disease. But our skin, our guts, and our mouths are teeming with several billion bacteria that cause no disease whatsoever. (Science writer Ed Yong’s seminal book I Contain Multitudes: The Microbes Within Us and a Grander View of Life provides a panoramic view of our intimate and generally symbiotic pact with bacteria.) In fact, bacteria are either harmless or actually helpful. In the gut, they aid digestion. On the skin, some researchers suspect, they inhibit colonization by much more harmful microbes. An infectious disease specialist once told me that humans were just “nice-looking luggage to carry bacteria around the world.” He might have been right.

And now the third branch: archaea. It may be the singularly most startling fact in the history of taxonomy that this full branch of living beings remained undiscovered until about fifty years ago. In the mid-1970s, Carl Woese, a professor of biology at the University of Illinois at Urbana-Champaign, used comparative genetics—the comparison of genes across various organisms—to deduce that we had misclassified not just some arcane microbe but rather an entire domain of life. For decades, Woese fought a spirited but lonely, bitter war that left him ragged at the edges. Taxonomy wasn’t just missing the point, he insisted, it was missing a whole living domain. Archaea, Woese argued, were not “almost like” bacteria or “almost like” eukaryotes. (“Almost like” is the taxonomist’s version of a parent saying to a child, “Go away, you’re bothering me.”)

The words organism and organized share a common root. Both come from the Greek organon (later the Latin organum), an instrument or tool, or even a method of logic, designed to achieve something. If the cell is the basic unit of life—the living tool that forms the organism—then what is it “designed” to do?

These, then, are among the first and most fundamental properties of the cell: autonomy, reproduction, and development.I For centuries, we regarded these fundamental features as impregnable. The interior anatomy of the cell and its internal homeostasis were, well, interior and internal—black boxes. Reproduction and development occurred within the womb—another black box. But as we deepen our understanding of the cell, we find ourselves able to pry open these black boxes and alter the fundamental properties of living units. Can we repair a cell’s subunit that happens to be defective in function—and if so, to what extent? Can we build a cell with a different kind of interior milieu, different substructures, and therefore different properties? And if we enable human reproduction outside the womb, as we have already, will such an artificially created embryo be open to genetic manipulation? What, then, are the permissible limits, and perils, of tampering with the first, fundamental properties of life?

To begin with, a bounded, autonomous living unit—a “closed unit” that bears the laws that govern its existence—must have a boundary. It is the membrane that defines the boundary; the outer limits of the self. Bodies are bound by a multicellular membrane: the skin. So is the psyche, by another membrane: the self. And so are houses and nations. To define an internal milieu is to define its edge—a place where the inside ends, and the outside begins. Without an edge, there is no self. To be a cell, to exist as cell, it must distinguish itself from its nonself. But what is the boundary of a cell? Where does one cell end and another begin? It also begins and ends with a membrane that surrounds it.

Looking but not seeing. Sight—real sight—requires insight.

Let us begin with a fact that is both strikingly self-evident to a cell therapist and startling to someone outside the field: in vitro fertilization (IVF) is cell therapy. It is, in fact, among the most common cell therapies in human use. It has been a reproductive option for more than four decades and has produced roughly eight to ten million children. Many of those IVF babies are now adults with children of their own—typically produced without any need for in vitro fertilization. It has become so familiar, indeed, that we don’t even imagine it as cellular medicine, although, of course, it is precisely that: the therapeutic manipulation of human cells to ameliorate an ancient and aching form of human suffering: infertility.

Oswald, serving in the French front of the US Medical Corps, began to think of blood as a mobile organ—restless, not just inside humans or between humans, but between national borders and battlefields. He collected O group blood from convalescing soldiers at one site, then packed sterile two-liter glass bottles containing citrated, dextrose-supplemented blood in ammunition boxes filled with sawdust and ice, and shipped them to the battlefield for use. In effect, Captain Oswald had established one of the first blood banks. (A more formal bank would be set up in Leningrad in 1932.) Gratitude poured in. “On the 13th June, you took my leg off above the knee,” one soldier wrote to Major Bruce Robertson in 1917, “and until I received blood from someone else, you considered the betting about 3 to 1 on my pegging out…. Can you find time to let me know the name and address of the man who gave me blood? I should much like to write to him.”

Oh; that's sweet. ☺️

By the time World War II broke out just two decades later, banking, matching, and transfusion had become common practices in the field. Compared to the First World War, the mortality rate of wounded soldiers who reached a field hospital nearly halved—due partly to blood transfusions. In the early 1940s, the United States, aided by the American Red Cross, launched a nationwide program for blood donation and banking. By the end of the war, the Red Cross had collected thirteen million units of blood, and within a matter of years, the US blood system had fifteen hundred hospital-based blood banks. There were forty-six community donation centers, and thirty-one regional centers to donate blood. As one writer put it in a 1965 issue of the journal Annals of Internal Medicine, “War has never lavished gifts on humanity; an exception may be made for the impetus and popularization of the use of blood and plasma… attributable to the Spanish Civil War, World War II, and the Korean conflict.” Perhaps more than any other intervention, transfusion and banking—cellular therapy—stands as the most significant medical legacy of the war.

Many of the crucial proteins that enable the formation, trafficking, and circulation of so-called bad cholesterol are synthesized in the liver. Recall the gene-editing technologies used by He Jiankui to alter genes in human embryos—in essence, rewriting the genetic script of human cells. Neither Sek nor Verve has any interest or desire to change genes in human embryos; rather, they hope to use gene-editing technologies to inactivate the genes that encode for these cholesterol-related proteins in human liver cells—and that, too, without removing the liver from the body. Scientists at Verve have devised ways to insert catheters into the arteries leading to the liver. (The dexterity that Sek learned from decades of practice in cardiology helped.) These catheters will deliver gene-editing enzymes, loaded inside tiny nanoparticles, to the organ. Once these particles off-load their cargos inside the liver cells, the gene-editing enzymes will change the scripts of genes that aid and abet cholesterol metabolism, thereby drastically decreasing the amount of circulating cholesterol in the blood—in essence, activating the LDL metabolizing pathways. It’s a one-and-done infusion. Once the genes have been altered, they are altered for life. If successful, Verve’s gene therapy would transform you into a human with permanently lowered cholesterol level, permanently protected from coronary artery disease, permanently safe from myocardial infarction. It would be the ultimate feat of cellula...

That seems like it's courting unforseen consequences. The "so-called bad cholesterol" (to literally quote the text) is there for a reason and only pathological under certain artificially generated modern circumstances. A gene therapy to permanently rid a body it feels like looking at a not inconsiderable mess but deciding it should be cleaned up with a death star.

In the 1840s, a French pathologist in Paris, Gabriel Andral, looked down a microscope and found what two generations of microscopists had seemingly missed: yet another type of cell in blood. Unlike red blood cells, these cells lacked hemoglobin, possessed nuclei, and were irregularly shaped, occasionally with pseudopods—fingerlike extensions and projections. They were termed “leukocytes,” or white blood cells. (They are “white” only in the sense that they are not “red.”)

An astonishing feature of this early immune response is that its cells, neutrophils and macrophages among them, are intrinsically armed with receptors that recognize proteins (and other chemicals) found on the surface or the interior of some bacterial cells and viruses. Pause for a moment to consider that fact. We—multicellular animals—have been at war with microbes for such a long time in evolutionary history that, like ancient, conjoined enemies, we’ve been defined by each other. We are in a lockstep dance. Our first-responder immune cells carry pattern-recognition receptors that are inherently designed to latch on to molecules found in microbial cells or injured cells that are not specific to a specific pathogen (Streptococcus, say) but are broadly present in all bacteria and viruses. Some receptors recognize a protein found in bacterial cell walls but not in animal cell membranes. Some bind to a protein found uniquely in the swimming tails of some bacteria. Yet others sense signals sent out by cells that have been infected by viruses. Speaking generally, these receptors come in two classes: those that recognize “damage-associated molecular patterns” (substances released upon cellular damage) and those that sense “pathogen-associated molecular patterns” (components of microbial cells). In short, they sniff around the body looking for patterns of injury and infection—substances that signal invasion and pathogenicity. When a neutrophil or a macrophage meets a bacterial ce...

The various sizes and shapes of pustules led to the European name for smallpox: variola, from the word variation. And the immunization against the pox was called variolation.

In the early eighteenth century, Lady Mary Wortley Montagu, the wife of the British ambassador to Turkey, was herself affected by the pox, her perfect skin left pitted with lesions. In Turkey, she witnessed variolation in practice and, on April 1, 1718, wrote to her lifelong friend Mrs. Sarah Chiswell in wonder: There is a set of old women, who make it their business to perform the operation, every autumn, in the month of September, when the great heat is abated…. The old woman comes with a nut-shell full of the matter of the best sort of small-pox, and asks what vein you please to have opened. She immediately rips open that you offer to her, with a large needle (which gives you no more pain than a common scratch) and puts into the vein as much matter as can lie upon the head of her needle, and after that, binds up the little wound with a hollow bit of shell, and in this manner opens four or five veins. Then the fever begins to seize them, and they keep their beds two days, very seldom three. They have very rarely above twenty or thirty in their faces, which never mark, and in eight days time they are as well as before their illness. Where they are wounded, there remains running sores during the distemper, which I don’t doubt is a great relief to it. Every year, thousands undergo this operation, and the French ambassador says pleasantly, that they take the small-pox here by way of diversion, as they take the waters in other countries. There is no example of any one that ha...

Yes, but it was also a massive scandal at the time.

Yet this story, retold and recycled in textbooks, is potentially riddled with misattributions. The virus carried in Sarah Nelmes’s pox lesions was likely horsepox, not cowpox. In a book he self-published in 1798, Jenner acknowledged the fact: “Thus the Disease makes its progress from the Horse [as I conceive] to the nipple of the Cow, and from the Cow to the Human Subject.” Furthermore, Jenner might not have been the first vaccinator in the Western world: in 1774, Benjamin Jesty, a hefty, prosperous farmer from Yetminster village in the county of Dorset, also convinced by the stories of dairymaids who contracted cowpox and then appeared to be immune to smallpox, supposedly harvested lesions from the udder of an infected cow, and inoculated his wife and two sons. Jesty became an object of ridicule among physicians and scientists—yet his wife and children survived the smallpox epidemic without catching the disease.

Not to mention at least one person - I believe it was Cotton Mather, though it's entirely possible my memory's wrong - in Massachusetts.

the story of vaccination is not the story of progressive scientific rationalism. Its hero is not Addison, who first found white blood cells. Nor is it Metchnikoff, whose discovery of phagocytes might have opened a door on protective immunity. Not even the scientists who discovered the innate response to bacterial cells merit being lauded as the heroes behind this medical milestone.III Rather, its history is one of veiled hearsay, gossip, and myth. Its heroes are nameless: the Chinese doctors who air-dried the first pox pustules; the mysterious sect of worshippers of Shitala who ground viral matter with boiled rice and inoculated it into children; the Sudanese healers who came to discern the ripest lesions.

Sometime in the near future, we will learn to pitch the innate immune system’s wrath against cancer cells; to calm it in the case of autoimmune diseases; to augment it to create a new generation of vaccines against pathogens. Once we teach our innate immune cells to attack malignant cells in humans, we will have invented an entirely new mode of cell therapy that harnesses inflammation. Perhaps we might describe it, metaphorically, as a pox on cancer.

In 1940, the fabled chemist at the California Institute of Technology, Linus Pauling, proposed an answer—an answer so wrong that it would eventually point to the truth. Pauling’s scientific achievements were legendary. He had solved an essential feature of protein structure, and described the thermodynamics of the chemical bond—but he could also be spectacularly off-track. There’s a story that quantum physicist Wolfgang Pauli, as notoriously cantankerous as he was brilliant, supposedly read a student’s paper and remarked that it was “so bad that it was not even wrong.” Pauling, with his daring, off-the-wall theories, often lobbed casually during scientific meetings, achieved the converse provocation: his hypotheses or models were sometimes so wrong that they weren’t even bad. Pauling’s colleagues had gotten used to his madcap theories; they even cherished them. By analyzing the internal contradictions of Pauling’s models—in other words, by reasoning through what was wrong with the proposal, and why it couldn’t be correct—they often found that they could arrive at the real mechanism, the truth.

There was no point probing further. An impenetrable sheet of privacy stood between us. In his 1981 novel Midnight’s Children, Salman Rushdie writes of a doctor who is allowed to examine his patient, a young woman, only through a hole in a white sheet of cloth. It seemed, at times, that I could visualize my patient only through a hole in a sheet of cloth—of what? Homophobia? Denial? Sexual shame? Addiction?

It is one of the philosophical enigmas of immunity that the self exists largely in the negative—as holes in the recognition of the foreign. The self is defined, in part, by what is forbidden to attack it. Biologically speaking, the self is demarcated not by what is asserted but by what is invisible: it is what the immune system cannot see. “Tat Twam Asi.” “That [is] what you are.”

As my eyes darted from one cell to another, I thought about the trajectory of this book. Our story has moved. Our vocabulary has shifted. Our metaphors have changed. Flip back a few pages, and we imagined the cell as a lone spaceship. Then, in the chapter “The Dividing Cell,” the cell was no longer single but became the progenitors of two cells, and then four. It was a founder, the originator of tissues, organs, bodies—fulfilling the dream of one cell becoming two and four. And then it transformed into a colony: the developing embryo, with cells settling and positioning themselves within the landscape of an organism. And blood? It is a conglomerate of organs, a system of systems. It has built training camps for its armies (lymph nodes), highways and alleys to move its cells (blood vessels). It has citadels and walls that are constantly being surveyed and repaired by its residents (neutrophils and platelets). It has invented a system of identification cards to recognize its citizens and eject intruders (T cells) and an army to guard itself from invaders (B cells). It has evolved language, organization, memory, architecture, subcultures, and self-recognition. A new metaphor comes to mind. Perhaps we might think of it as a cellular civilization.

The studies began to fit together, like pieces of a jigsaw puzzle: the virus was most deadly when it infected a host whose early antiviral response had been functionally paralyzed—like “a raider that had come into an unlocked house,” as one writer described it. The pathogenicity of SARS-COV2, in short, perhaps lay precisely in its ability to dupe cells into believing that it is not pathogenic. More data poured in. The infected host cell, with its impaired ability to send out an initial danger signal, wasn’t simply an “unlocked house.” Rather, it was an unlocked house with not one but two dysfunctional alarm systems. It couldn’t summon an early alert—type 1 interferon, among the signals—but as the house burned, the cell yanked the trigger on a powerful, second alarm, sending out a separate series of danger signals—cytokines—to summon immune cells. An uncoordinated army of cells—confused, bamboozled soldiers—surged into the sites of infection and started a carpet-bombing program. It was too much, too late. The trigger-happy immune cells poured out a fog of toxins to contain the virus. The war against the virus—as much as the virus itself—became an escalating crisis. The lungs were bogged with fluid; debris from dead cells clogged the air sacs. “There appears to be a fork in the road to immunity to Covid-19 that determines disease outcome,” Iwasaki told me. “If you mount a robust innate immune response during the early phase of infection [presumably via an intact type 1 inter...

That reminds me of one the reasons the 1918 pandemic was so bad for otherwise healthy, young to middle aged people: their immune systems went WAY OVERBOARD in trying to kill the virus and ended up causing too much collateral damage to the body.

There’s an alternative story—a triumphalist narrative—that can also be told about the pandemic. It goes this way: immunologists and virologists, building on decades of investigation into the fundamentals of cell biology and immunity, developed vaccines against SARS-COV2 in record time—some less than a year after the man from Wuhan had entered the Seattle clinic. Many of these vaccines functioned with entirely new methods of eliciting immunity—an altered chemical form of mRNA, for instance—again, using decades of knowledge of how immune cells detect foreign proteins, and how they might stave off infections. But 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.

The Brain—is wider than the Sky— For—put them side by side— The one the other will contain With ease—and you—beside— The Brain is deeper than the sea— For—hold them—Blue to Blue— The one the other will absorb— As sponges—Buckets—do— —Emily Dickinson, c. 1862

“It takes a courageous person,” the poet Kay Ryan once wrote, “to leave spaces empty”—and

Neural connections between the eyes and the brain are formed long before birth, establishing the wiring and the circuitry that allow a child to begin visualizing the world the minute she emerges from the womb. Long before the eyelids open, during the early development of the visual system, waves of spontaneous activity ripple from the retina to the brain, like dancers practicing their moves before a performance. These waves configure the wiring of the brain—rehearsing its future circuits, strengthening and loosening the connections between neurons. (The neurobiologist Carla Shatz, who discovered these waves of spontaneous activity, wrote, “Cells that fire together, wire together.”) This fetal warm-up act—the soldering of neural connections before the eyes actually function—is crucial to the performance of the visual system. The world has to be dreamed before it is seen.

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.

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

It’s tempting to think of the stem cell as an ancestral great-great-great-grandfather or -grandmother. Its progeny give rise to more progeny, resulting in a vast lineage that arises from a single great-great-great-grandfather cell. But to be a true stem cell, this must be the oddest of great-great-great-grandfathers. It must also give birth to a copy of itself that can maintain the replenishment of the lineage. This great-great-great-grandfather, besides birthing a child (that will go on to establish an enormous lineage), must also birth a copy of itself—an eternally alive twin. And once this self-renewing great-great-great-grandfather is born, the process of regeneration can become limitless. There’s a mythic quality to such a setup—and indeed, in myths, one often finds attempts by powerful kings or Gods to make backup twins (dolls, voodoo objects, souls secretly stored in animals, twin personhoods locked in amulets) to reboot themselves and their clan should something terrible happen. Like most real stem cells, these mythic doubles usually lie dormant—quiescent—until an injury wakes them up. And then they awake and reseed the whole clan. It results not in birth but rebirth.

Since Yamanaka’s discovery, for which he won the Nobel Prize in 2012, hundreds of labs have started working on iPS cells. The allure is this: you take your own cell—a skin fibroblast, or a cell from your blood—and you make it crawl backward in time and transform it into an iPS cell. And from that iPS cell, you can now make any cell you’d like—cartilage, neurons, T cells, pancreatic beta cells—and they’d still be your own. There would be no problem with histocompatibility. No immune suppression. No reason to worry about the guest turning immunologically against the host. And in principle, you could repeat the process infinitely—iPS into beta cell back to iPS cell into beta cell (to be fair, no one has tried this yet). The recursiveness, though, sets up yet another fantasy of a new human: one in whom every degenerated organ, or tissue, could be regenerated, and regenerated again, ad infinitum. I sometimes think of the Greek story of the Delphic boat. The boat is built of many planks. Bit by bit, the planks decay and are replaced by new ones, until all of them are new. But has the boat changed? Is it even the same boat?

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.

When I went to meet Sam P. in the hospital, in May 2018, I was asked to wait outside. He was nauseated and excused himself to use the bathroom. He composed himself, and a nurse helped him back to bed. It was nearing twilight, and he turned a bed lamp on. He asked the nurse if we might speak alone. “It’s over, isn’t it?” he said, looking straight at my face, his brain boring a direct hole into the core of my brain. “Be honest,” he said. Was it really over? I mulled over the question. Here we had the strangest of cases—some of his tumors were responding to the immunotherapy, while others remained obdurately recalcitrant. And every time we increased the dose of the immune drugs, an autoimmune hepatitis—horror autotoxicus of the liver—would push us back. It was as if each individual, metastatic tumor had acquired its own program of rebirth and resistance, each battening down in its own niche in his body, each behaving as if it were an independent community of colonists trapped in its own island. We were fighting on multiple fronts at the same time—winning some, losing others. And every time we applied an evolutionary pressure on the cancer—an immunotherapeutic drug, say—some cell escaped the pressure and set up a new recalcitrant colony again. I told him the truth. “I don’t know,” I said. “And I will not know, right till the very end.”

“We biomedical scientists are addicted to data, like alcoholics are addicted to cheap booze,” Michael Yaffe, a cancer biologist from MIT, wrote in the journal Science Signaling. “As in the old joke about the drunk looking under the lamppost for his lost wallet, biomedical scientists tend to look under the sequencing lamppost where the ‘light is brightest’ [because that’s where it’s easiest to see]—that is, where the most data can be obtained as quickly as possible. Like data junkies, we continue to look to genome sequencing when the really clinically useful information may lie someplace else.” Sequencing is seduction. It is data, not knowledge.

In his 2021 book on ecology and climate, The Nutmeg’s Curse: Parables for a Planet in Crisis, Amitav Ghosh recounts the story of an eminent professor of botany who accompanies a young man from a local village to guide him through a rain forest. The young man is able to identify each of the various plant species. His acumen stuns the professor, who compliments him on his knowledge. But the man is dejected. He “nods and replies with downcast eyes. ‘Yes, I’ve learned the names of all the bushes, but I’ve yet to learn the songs.’ ” Many readers might read the word song as metaphorical. But in my reading, it’s far from a metaphor. What the young man laments is that he hasn’t learned the interconnectedness of the individual inhabitants of the rain forest—their ecology, interdependence—how the forest acts and lives as a whole. A “song” can be both an internal message—a hum—and, equally, an external one: a message sent out from one being to another to signal interconnectedness and cooperativity (songs are often sung together, or to one another). We can name cells, and even systems of cells, but we are yet to learn the songs of cell biology.

there are still gaps in our understanding of the interconnectedness of cells. We are still living in a world where we imagine the cell, as Leeuwenhoek did, as a “living atom”—unitary, singular, and isolated, a spaceship floating in body-space. Until we leave that atomistic world, we will not know, as the English surgeon Stephen Paget asked, why the liver and spleen are the same size, are anatomical neighbors, possess virtually the same flux of blood—and yet one (the liver) is among the most frequent sites of cancer metastases, while the other (the spleen) rarely has any? Or why patients with certain neurodegenerative diseases—Parkinson’s among them—have a markedly lower risk of cancer. Or why, as Helen Mayberg told me, the patients who describe their depression as an “existential ennui” (her words) typically do not respond to deep brain stimulation, while those that describe themselves as “falling into vertical holes” often do. Like the dejected man in the rain forest, we have learned the names of the bushes, but not the songs that move between the trees.

A variant of postmodern scientific thought threw the equations, with the blackboards they were written on, into the trash; the baby went with the bathwater. But that, too, is an equal and opposite nonsense: a Newtonian ball thrown into Newtonian space does follow Newtonian laws. The laws that govern the ball are as real and tangible as they were during the conception of the universe. By the same logic, a cell, and a gene, are real. It’s just that they aren’t “real” in isolation. They are fundamentally cooperative, integrating units, and together, they build, maintain, and repair organisms. I cannot help you hold both ideas in your head at the same moment. But perhaps some experience with non-Western philosophies might help here: “cooperative” and “unitary”—selfless and self-regarding—are not mutually exclusive ideas. They exist in parallel. Universal principles satisfy us—one equation good—because they satisfy our belief in an ordered universe. But why must “order” be so soldierly, so singular, so unifest (as opposed to manifest)? Perhaps one manifesto for the future of cell biology is to integrate “atomism” and “holism.” Multicellularity evolved, again and again, because cells, while retaining their boundaries, found multiple benefits in citizenship. Perhaps we, too, should begin to move from the one to the many. That, more than any other, is the advantage of understanding cellular systems, and, beyond that, cellular ecosystems.

Systems of cells with specialized functions, communicating with each other through short- and long-range messages, can achieve powerful physiological functions that individual cells cannot achieve—for example, the healing of wounds, the signaling of metabolic states, sentience, cognition, homeostasis, immunity. The human body functions as a citizenship of cooperating cells. The disintegration of this citizenship tips us from wellness into disease.

Beyond understanding cells in isolation, deciphering the internal laws of cellular citizenship—tolerance, communication, specialization, diversity, boundary-formation, cooperation, niches, ecological relationships—will ultimately result in the birth of a new kind of cellular medicine.