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

by Siddhartha Mukherjee

[Life] is a continuing rhythmic movement, of the pulse, of the gait, even of the cells. —Friedrich Nietzsche

“Elementary,” he said. “It is one of those instances where the reasoner can produce an effect which seems remarkable to his neighbor, because the latter has missed the one little point which is the basis of the deduction.” —Sherlock Holmes to Dr. Watson, in Sir Arthur Conan Doyle, “The Crooked Man”

A life within a life. An independent living being—a unit—that forms a part of the whole. A living building block contained within the larger living being.

Animals and plants—as seemingly different as living organisms could be. Yet, as both Schwann and Schleiden had noticed, the similarity of their tissues under the microscope was uncanny. Schwann’s hunch had been right. That evening in Berlin, he would later recall, the two friends had converged on a universal and essential scientific truth: both animals and plants had a “common means of formation through cells.”

But then things turned: April 2017 was a cruel month. The T cells that attacked his tumor turned on his own liver, provoking an autoimmune hepatitis, an inflammation of the liver that could barely be controlled with immune-suppressive drugs.

As the T cells killed the cancer cells, they were releasing a storm of these chemical messengers, like a rioting crowd disgorging inflammatory pamphlets on a rampage.

And finally, a cell is a dividing machine. Molecules within the cell—proteins, again—initiate the process of duplicating the genome. The internal organization of the cell changes. Chromosomes, where the genetic material of a cell is physically located, divide. Cell division is what drives growth, repair, regeneration, and, ultimately, reproduction, among the fundamental, defining features of life.

(if cloudless Italy was a land made for telescopes, then foggy, dark England seemed custom-made for microscopes)—and

As I wrote furiously from the early months of 2020 into 2022, the Covid-19 pandemic continued wildfiring its way throughout the globe. My hospital, my adopted city of New York, and my homeland overflowed with the bodies of the sick and the dead. By February 2020, the ICU beds at Columbia University Medical Center, where I work, were full of patients drowning in their own secretions, with mechanical ventilators forcing air in and out of their lungs. The early spring of ’20 was particularly bleak: New York turned into an unrecognizable, windblown metropolis of empty byways and avenues, where people hid from people. India’s most lethal surge hit almost a year later in April and May 2021. Bodies were burned in parking lots, back alleyways, slums, and children’s playgrounds. At the crematoria, the fires burned so often and so briskly that the metal grids holding the bodies corroded and melted.

Covid was bad 💯 epistemic

Both of us, you and I, began as single cells. Our genes are different, albeit marginally. The way our bodies develop are different. Our skin, our hair, our bones, our brains are all built differently. Our life experiences vary widely. I lost two uncles to mental illness. I lost a father to a deadly spiral following a fall. A knee to arthritis. A friend—so many friends—to cancer. And yet, despite all the yawning gaps between our bodies and experiences, you and I share two features. First, we arose from a single-celled embryo. And second, from that cell came multiple cells—those that populate your body and mine. We are built of the same material units and are akin to two different nuggets of matter built from the same atoms. What are we made of? Some ancients believed that we were created by menstrual blood that had congealed into bodies. Some believed we came preformed: mini-beings that just expanded over time, like human-shaped balloons blown up for a parade. Some thought humans were sculpted from mud and river water. Some thought we transformed gradually in the womb from tadpole-like beings to fish-mouthed creatures, and, finally, into humans. But if you looked down a microscope at your skin and mine, or your liver and mine, you would find them strikingly alike. And you’d realize that all of us were, in fact, built out of living units: cells. The first cell gave rise to more cells, and then divided to form even more, until our livers and guts and brains—all the elaborate ...

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

The basement of Paris’s hospital Hôtel-Dieu, where decaying human cadavers were dissected, was a dingy, airless, badly lit space with half-feral dogs roaming underneath the gurneys to gnaw on the drippings—a “meat market,” as Vesalius would describe one such anatomical chamber. The professors sat on “lofty chairs [and] cackle like jackdaws,” he wrote, while their assistants hacked and tugged through the body at random, eviscerating organs and parts as if pulling out cotton stuffing from a toy.

The graves at the Cemetery of the Innocents, often open to the air, with bodies ground to the bone, provided perfectly preserved specimens for skeletal drawings.

The miasmas carried particles of decaying matter called miasmata that somehow entered the body and forced it to decay. (A disease such as malaria still carries that history, its name created by joining the Italian mala and aria to form “bad air.”)

Early health reformers thus concentrated on sanitary reform and public hygiene to prevent and cure illness. They dug sewage systems to dispense waste, or opened ventilation ducts in homes and factories to prevent the contagious fog of miasmata from accumulating indoors. The theory seemed to be fogged by an indisputable logic. Many cities, undergoing rapid industrialization and unable to deal with the influx of wageworkers and their families, were malodorous arenas of smog and sewage—and disease seemed to track the worst-smelling, most populated areas. Resurgent waves of cholera and typhus stalked the poorer parts of London and its vicinities, such as the East End (now glistening with shops and restaurants selling high-end linen aprons and expensive bottles of single-distillery gin). Syphilis and tuberculosis were rampant. Childbirth was a terrifying event, with a distinct likelihood of ending not in birth but in death—of the infant, the mother, or both. In the wealthier parts of town, where the air was clean, and sewage adequately discarded, health prevailed, while the poor, who lived in miasma-filled areas, inevitably succumbed to illness. If cleanliness was the secret to health, then disease must be a condition of uncleanliness or contamination.

the sum of the parts, there are only the parts. The world must be measured by eye. —Wallace Stevens

Highbrow science was born from lowbrow tinkering.

animalcules,” he called them. Telescopists had seen macroscopic worlds—the blue-tinged moon, gaseous Venus, ringed Saturn, red-flecked Mars—but no one had reported a marvelous cosmos of a living world in a raindrop. “This was to me among all the marvels that I have discovered in nature the most marvelous among them all,” he wrote in 1676. “No greater pleasure has yet come to my eye than these spectacle of the thousands of living creatures in a drop of water.”II He wanted to look more, to build finer instruments to visualize this captivating new universe of living beings. And so Leeuwenhoek purchased the highest-quality beads and globules of Venetian glass and then ground and polished them laboriously into perfectly lenticular shapes (some of his lenses, we now know, were made by stretching a rod of glass into a thin needle on a live flame, breaking the end, and then letting the needle “bubble” into a lens-shaped globule). He mounted these lenses on thin metal plates, crafted of brass, silver, or gold, each with an increasingly complex system of miniature armatures and screws to move parts of the instrument up and down and attain perfect focus. He made nearly five hundred such scopes, each a marvel of meticulous tinkering. Were such creatures present in other samples of water

In 1677, Leeuwenhoek observed human spermatozoa, “a genital animalcule,” in his semen as well as in a sample from a man with gonorrhea. He found them “moving like a snake or an eel swimming in water.” Yet despite his ardor and productivity, the cloth merchant was notoriously reluctant to let observers or scientists examine his instruments.

In 1665, nearly a decade before Leeuwenhoek published his letter describing animalcules in water, Robert Hooke, an English scientist and polymath, had also seen cells—although not live ones, and nowhere as diverse as Leeuwenhoek’s animalcules. As a scientist, Hooke, perhaps, was quite the opposite of Leeuwenhoek. He had been educated at Wadham College in Oxford, and his intellect ranged widely, foraging through different worlds of science and consuming whole realms as he moved. Hooke was not just a physicist but also an architect, a mathematician, a telescopist, a scientific illustrator, and a microscopist. Unlike most gentleman scientists of his era—men from wealthy families who could afford to ruminate about the natural sciences without ruing the next paycheck—Hooke came from an indigent English family. As a scholarship student at Oxford, he had survived by apprenticing with the eminent physicist Robert Boyle. By 1662, even as Boyle’s subordinate, he had established himself as a powerfully independent thinker and found employment

“The Eyes of a Fly… appear almost like a Lattice,”

block of material. “I took a good clear piece of cork,” he explained in Micrographia, “and with a pen-knife sharpened as keen as a razor, I cut a piece of it off, and thereby left the surface of it exceeding smooth, then examining it very diligently with a microscope, methought I could perceive it to be a little porous.” These pores or cells were not very deep but consisted of “a great many little boxes.” In short, this piece of cork was created out of a regular assemblage of polygonal structures with discrete, repetitive “units” that were collected together to form the whole. They resembled the honeycombs in a hive—or the living quarters of a monk.

“Nay, we may yet carry it farther, and discover in the smallest particle of this little world a new inexhausted fund of matter, capable of being spun out into another universe.”

Hooke’s interest in microscopy eventually dwindled. His peripatetic intellect needed to roam widely, and he returned to optics, mechanics, and physics. Indeed, Hooke’s interest in virtually everything may have been his critical failing. The Royal Society’s motto, Nullius in verba, translated loosely as “Take no one’s word for evidence,” was his personal mantra. He loped from one scientific discipline to the next, offering potent insights, believing no one’s word, claiming dominion over critical parts of a science, but never asserting complete authority over any one subject. He had built himself on the model of the Aristotelian philosopher-scientist—an inquirer into all matters of the world, an adjudicator of all evidence—rather than the contemporary vision of the scientist as the authority on a single subject, and his reputation suffered as a result.

Epistemic hubris

In the history of biology, there are often valleys of silence that follow the peaks of monumental discoveries. Gregor Mendel’s discovery of the gene in 1865 was followed by what one historian called “one of the strangest silences in the history of science”: genes (or “factors” and “elements,” as Mendel loosely called them) were not mentioned for nearly forty years, before being rediscovered in the early 1900s. In 1720, the London physician Benjamin Marten reasoned that tuberculosis—phthisis, or consumption, as it was then called—was a contagious disease of the respiratory system, likely carried by microscopic organisms. He called the potential contagious elements “wonderfully minute living creatures,” and contagium vivum, or “living contagion.” (Note the word living.) Marten would almost have become the father of modern microbiology had he deepened his medical discoveries, but it would take nearly a century before microbiologists Robert Koch and Louis Pasteur each linked disease and putrefaction to the microbial cell.

So convinced were some alchemists about the pre-existence of all human forms in a fetus that they thought that incubating a chicken egg with sperm would generate a fully formed human, since the instructions to build one from scratch were already present in the sperm.

In his book Microscopical Researches,

Great title

All cells come from other cells (Omnis cellula e cellula). Normal physiology is the function of cellular physiology. Disease, the disruption of physiology, is the result of the disrupted physiology of the cell. These five principles would form the pillars of cell biology and cellular medicine. They would revolutionize our understanding of the human body as assemblages of these units. They would complete the atomist conception of the human body, with the cell as its fundamental, “atomic” unit. 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.”

Epistemic moral hippocratic

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.

Gross mass Pathology ! Epistemic Republican Party

The junior residents and nurses could not find a vein in his hands to insert an intravenous line, and when I was asked to place a large-bore central IV line in his jugular vein to deliver antibiotics and fluids, it was as if my needle were piercing dried parchment. His skin had a papery, translucent quality that nearly crackled as I touched it. M.K. had been diagnosed with a particular variant of severe combined immunodeficiency (acronymed SCID), in which both B cells (white cells that make antibodies) and T cells (that kill microbially infected cells and help mount an immune response) are dysfunctional. A grotesque English garden of microbes—some common, some exotic—grew out of his blood: Streptococcus, Staphylococcus aureus, Staphylococcus epidermidis, weird fungal varieties, and rare bacterial species whose names I could not even pronounce. It was as if his body had been transformed into a living petri dish for microbes.

Fire 🔥

Every time I think of M.K.’s case and my memories of him in his hospital room—his father trudging to Boston’s North End in the snow to bring him his favorite Italian meatballs, only to find them untouched by the young man’s bedside, and the mystified, befuddled doctors writing medical note after note with multiple question marks crisscrossing the pages—I also think of Rudolf Virchow, and the “new” pathology that he advanced.

It was hard, after all, to reconcile a divine corpse ascending to the heavens with decomposing pieces of it falling off like corporeal jetsam.

Fire 🔥

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 the students and the surgeons wash their hands with chlorine and water before entering the maternity wards. Semmelweis kept careful records of the deaths in the two clinics. The impact was astonishing, with the mortality rate in the first clinic declining by 90 percent. In April 1847, the mortality rate had been nearly 20 percent: one in five women died of childbed fever. By August, after rigorous hand washing had been instituted, the mortality among the new mothers had declined to 2 percent.

Ultimate dunk epistemic

occurs to me, as I write this, how much this framework—germs, cells, risk—still scaffolds the diagnostic art in medicine. Each time I see a patient, I realize, I am probing the cause of his or her disease through three elemental questions. Is it an exogenous agent, such as a bacterium or virus? Is there an endogenous disturbance of cellular physiology? Is it the consequence of a particular risk, be it exposure to some pathogen, a family history, or an environmental toxin? Years ago, as a young oncologist,

Clinical epistemic

But there is one question that we will not and, perhaps, cannot answer. The origin of the modern cell is an evolutionary mystery. It seems to have left only the scarcest of fingerprints of its ancestry or lineage, with no trace of a second or third cousin, no close-enough peers that are still living, no intermediary forms. Lane calls it an “unexplained void… the black hole at the heart of biology.”

These, then, are among the first and most fundamental properties of the cell: autonomy, reproduction, and development.I

The pioneering studies of Palade, Porter, and Claude threw open a new world of subcellular anatomy. The twinning of two ways of seeing—microscopy and biochemistry—was synergistic. As biologists used these methods on cells, they found dozens of such functional, anatomically defined subcellular structures. The Belgian biologist Christian de Duve, yet another Rockefeller Institute scientist, discovered an enzyme-laden structure called a lysosome. Like a cellular “stomach,” it digests worn-out cellular parts, as well as invading bacteria and viruses. Plant cells contain structures called chloroplasts, the sites of photosynthesis, the conversion of light into glucose. Chloroplasts, like mitochondria, carry their own DNA, again suggesting an origin in microbes that were engulfed by other cells. There is a membrane-bound structure called a peroxisome, another of de Duve’s discoveries, where some of life’s most dangerous reactions—for instance, the oxidation of molecules—is sequestered, and where hydrogen peroxide, an intensely reactive chemical, is generated. Were the peroxisome to open up and release its internal poisons, the cell would be attacked by its own reactive contents. It is the chalice, filled with poisons to metabolize other poisons, that the cell keeps carefully closed.

The nucleus, as I mentioned before, houses the organism’s genome, made of long stretches of deoxyribonucleic acid. The DNA double helix is elaborately folded and packaged around molecules called histones, and tightened and wound further into structures called chromosomes. If a single cell’s DNA could be stretched out straight, like a wire, it would measure six and a half feet. And if you could do that for every cell in the human body and laid all of that DNA end to end, it would stretch from the Earth to the sun and back again more than sixty times. String together all the DNA in every human being on the planet, and it would reach the Andromeda galaxy and back nearly two and half times.

A major point of physiological “activity,” paradoxically, was to enable stasis. Don’t just do something, stand there.

!

The discovery of functional anatomy enabled an integrated view of the cell and, by extension, of the defining features of life. A cell, as noted before, is not just a system of parts sitting next to parts, just as a car is not a carburetor sitting next to an engine. It is an integrating machine that must amalgamate the functions of these individual parts to enable the fundamental features of life. Between 1940 and 1960, scientists began to integrate the separate parts of the cell to understand how an autonomous living unit might function and become “living.”

Vitality epistemic

scientists had used these spiny, globular creatures, with their erotic tongues of flesh (Who ever thought of eating them?) as model systems to study fertilization, cell division, and embryology.

hospital, she would later cradle the first IVF baby. In 1985, she died of melanoma at just thirty-nine years of age, never able to fully garner the scientific recognition due to her. The study set off a public, scientific, and medical furor almost immediately. Attacks came from all sides at once. Some gynecologists did not consider infertility a disease. Reproduction, they argued, was not a requirement for wellness, so why define its absence as an “illness”? As one historian wrote: “It is perhaps difficult now to comprehend the complete absence of infertility from the consciousness of most gynaecologists in the UK at the time, of whom Steptoe was a remarkable exception…. Overpopulation and family planning were seen as dominant concerns, and the infertile were ignored as, at best, a tiny and irrelevant minority and, at worst, as a positive contribution to population control.” Much of the gynecological research in the United Kingdom and the United States focused on contraception—that is, bringing fewer babies into the world. In America, one scientific paper noted, “contraceptive development research increased over 6-fold between 1965 and 1969, and private philanthropic funding went up 30 times.” Religious groups, in turn, pointed to the special status of the human embryo: to produce one in a laboratory petri dish, intended for transfer into a human body, was to violate the most inviolable laws of “natural” human reproduction. And ethicists were hyperconscious of the legacy o...

In other words, you can cull, or remove, embryos from a set of permutations, but you cannot make embryos with new (de novo) sets of genes. You get what you get (and you don’t get upset): permutations of genes from both parents, but nothing outside those predetermined combinations.

“Honestly, I thought, This is fake, right? This is a joke,” she recalled. “ ‘Babies born.’ Who puts that in a subject line of an e-mail of that kind of import? It just seemed shocking, in a crazy, almost comedic, way.”

Cochlear implants can restore some hearing of speech, but, oddly, not music; what’s more, patients with implants typically require months of rehabilitation.

The next series of events represents the true marvel of embryology. The tiny cluster of cells hanging from the walls of the cellular balloon, the inner cell mass, divides furiously and begins to form two layers of cells—the outer one called the ectoderm, and the inner called the endoderm. And about three weeks after conception, a third layer of cells invades the two layers and lodges itself between them, like a child squeezing into bed between her parents. It’s now the middle layer, called the mesoderm. This three-layered embryo—ectoderm, mesoderm, endoderm—is the basis of every organ in the human body. The ectoderm will give rise to everything that faces the outer surface of the body: skin, hair, nails, teeth, even the lens of the eye. The endoderm produces everything that faces the inner surface of the body, such as the intestines and the lungs. The mesoderm handles everything in the middle: muscle, bone, blood, heart.

The embryo is now ready for the final sequence of activities. Within the mesoderm, a series of cells assemble along a thin axis to form a rodlike structure called the notochord, which spans from the front of the embryo to its back. The notochord will become the GPS of the developing embryo, determining the position and axis of the internal organs as well as secreting proteins called inducers. In response, just above the notochord, a section of the ectoderm—the outer layer—invaginates, folding inward and forming a tube. This tube will become the precursor of the nervous system, made up of the brain, spinal cord, and nerves. In one of embryology’s many ironies, having set up the framework of the embryo, the human notochord will lose its prominence and function between embryonic development and adulthood. Its only cellular remnant in the adult human body is the pulp that remains stuck between the skeletal bones. In the end, the master maker of the embryo is trapped inside the bony prison of the very creature it has created.

As the increasingly acrimonious Merrell-Kelsey battle was unfolding in Washington, DC, more ominous reports began to trickle in from Europe. Women who had been prescribed the drug in Britain and France during their pregnancies began to notice severe congenital malformations in their babies. Some had malformed urinary systems. Some had heart problems. Some had intestinal defects. The most visibly horrific manifestation was that some babies were born with severely shortened limbs, while some had no limbs at all. All in all, about eight thousand malformed babies would be reported in the next few years, and another seven thousand may have died in utero—both likely severe underestimates of the actual degree of harm. Yet even as one alarming case report after another streamed in from Europe, Merrell remained icily sanguine about the drug. Despite Kelsey’s objections, the company had distributed the drug to about twelve hundred US physicians as an “investigational agent.” (Smith, Kline & French, another company, was also involved in the patient trial.)

Icily sanguine

In 1897, a young chemist named Felix Hoffman, working for the German pharmaceutical company Bayer, found a way to synthesize a chemical variant of salicylic acid. The medicine was called aspirin, or ASA, short for acetyl salicylic acid. (The name was drawn from the a in acetyl, and spir from Spiraea ulmaria, the plant from which salicylic acid was extracted.) Hoffman’s synthesis of aspirin was a marvel of chemistry, but the pathway from molecule to medicine was tortuous. A senior executive at Bayer, Friedrich Dresser, suspicious of aspirin, almost stopped production, claiming that the drug had an “enfeebling” effect on the heart. He preferred concentrating on the development of another drug—heroin—as a cough syrup and pain reliever. But Hoffman persisted obstreperously with the production of aspirin, pushing the Bayer executives to the brink of firing him.

But how did inoculation generate immunity, particularly long-term immunity? Some factor produced in the body must be able to counter the infection and also retain a memory of the infection over multiple years. Vaccination, as we will soon learn, generally works by inciting specific antibodies against a microbe. The antibodies come from B cells, and they are retained in the cellular memory of the host because some of these cells live for decades—long after the initial inoculum was introduced. We will turn to how B cells manage to achieve memory, and how T cells help, in the next chapter.