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

by Siddhartha Mukherjee

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.”

In 2010, when Emily Whitehead received her infusion of CAR (chimeric antigen receptor) T cells, or twelve years later, when the first patients with sickle cell anemia are surviving, disease-free, with gene-modified blood stem cells, we are transitioning from the century of the gene to a contiguous, overlapping century of the cell.

ultimately, in the cells, or systems of cells. In a sense, then, one might define life as having cells, and cells as having life.

What is a cell, anyway? In a narrow sense, a cell is an autonomous living unit that acts as a decoding machine for a gene. Genes provide instructions—code, if you will—to build proteins, the molecules that perform virtually all the work in a cell. Proteins enable biological reactions, coordinate signals within the cell, form its structural elements, and turn genes on and off to regulate a cell’s identity, metabolism, growth, and death. They are the central functionaries in biology, the molecular machines that enable life.I

Scientists have hunted for cells that use molecules other than DNA to carry their instructions—RNA, for instance—but so far, they’ve never found an RNA instruction-carrying cell.

A gene without a cell is lifeless—an instruction manual stored inside an inert molecule, a musical score without a musician, a lonely library with no one to read the books within it. A cell brings materiality and physicality to a set of genes. A cell enlivens genes.

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.

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

“True knowledge is to be aware of one’s ignorance,”

On May 26, 1675, the city of Delft was inundated by a storm. Leeuwenhoek, then forty-two, gathered some of the water from the drains of his rooftop, let it stand for a day, and then put a droplet under one of his microscopes and held it up to the light. He was instantly entranced. No one he knew had seen anything like it. The water was roiling with dozens of kinds of tiny organisms—“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

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.”

Hooke looked further and deeper for small, independent living units invisible to the naked eye. At a Royal Society assembly in November 1677, he described his microscopic observations on rainwater. The society recorded his observations: The first experiment there exhibited was the pepper-water, which had been made with rain-water… put whole into it about nine or ten days before. In this Mr. Hooke had all week discovered great numbers of exceedingly small animals swimming to and fro. They appeared the bigness of a mite through a glass, that magnified about a hundred thousand times in bulk; and consequently, it was judged, that they were a hundred thousand times less than a mite. Their shape was to appearance like a very small clear bubble of an oval or egg form; and the biggest end of this egg-like bubble moved foremost. They were observed to have all manner of motions to and fro in the water; and by all, who saw them, they were verily believed to be animals; and that there could be no fallacy in the appearance.

In 1687, Isaac Newton published Philosophiae Naturalis Principia Mathematica (Mathematical Principles of Natural Philosophy), a work so far-reaching in its depth and breadth that it shattered the past and shaped a new landscape for the future of science. Among its revelations: Newton’s law of universal gravitation. Hooke, however, argued that he had formulated the laws of gravitation earlier, and that Newton had plagiarized his observations.

In the late 1830s, in Berlin, the German scientist Robert Remak looked at frog embryos and chicken blood under a microscope. He was hoping to capture the birth of a cell, a particularly rare event in chicken blood, and so he waited. And waited. And then, late one evening, he saw it: under his scope, he watched a cell quiver, enlarge, bulge, and split in two, giving rise to “daughter” cells. Nothing less than a jolt of euphoria must have shot up Remak’s spine, for he had found incontrovertible evidence that developing cells arose from the division of preexisting cells—Omnis cellula e cellula, as Raspail had so inconspicuously tucked into an epigraph.I But Remak’s trailblazing observation was largely ignored, for as a Jew, he was denied full professorship at the university. (A century later, his grandson, a distinguished mathematician, would perish in the Nazi death camp at Auschwitz.)

In 1694, the Dutch microscopist Nicolaas Hartsoeker published drawings that showed miniature mini-humans in sperm, replete with head, hands, and feet all tucked origami-like into the sperm’s head, that he had apparently observed under the microscope. The riddle for cell biologists was to prove how a creature as complex as a human could emerge from a fertilized egg if there wasn’t a preformed template already present inside it.

Gradually, as the reach and generality of their claim became evident, Schleiden and Schwann proposed the first two tenets of cell theory: All living organisms are composed of one or more cells. The cell is the basic unit of structure and organization in organisms.

Virchow, then twenty-four years old and barely out of medical school, was called to consult on a medical case involving a fifty-year-old woman with implacable fatigue, a swollen abdomen, and a palpable, enlarged spleen. He drew a drop of blood from her and examined it microscopically. The sample exhibited an extraordinarily elevated level of white cells. Virchow called it leukocythemia and then simply leukemia—an abundance of white blood cells in blood.

Like hermits, microbes need only be concerned with feeding themselves; neither coordination nor cooperation with others is necessary, though some microbes occasionally join forces. In contrast, cells in a multicellular organism, from the four cells in some algae to the thirty-seven trillion in a human, give up their independence to stick together tenaciously; they take on specialized functions, and they curtail their own reproduction for the greater good, growing only as much as they need to fulfill their functions. When they rebel, cancer can break out. —Elizabeth Pennisi, Science, 2018

In Paris, in 1859, Louis Pasteur took Redi’s experiments further. He placed boiled meat broth in a swan-neck bottle, a round flask with a vertical neck bent into an S shape, like a swan’s neck. When Pasteur left the swan-neck bottle open to the air, the broth remained sterile: microbes in the air could not easily travel through the curve in the neck. But when he tipped the flask to expose the broth to the air, or cracked the swan neck, the broth grew out a turbid culture of microbes. Bacterial cells, Pasteur concluded, are carried in air and dust. Putrefaction, or rotting, was not caused by the inner decomposition of living creatures—or some visceral form of interior sin. Rather, decomposition only happened when these bacterial cells landed on the broth.

Koch took a droplet of blood from an anthrax-infected cow, made a tiny slit in the tail of a mouse with a sterile wooden sliver, and waited. It remains an incredible, if inexplicable, lapse in the history of biology that, until 1876, no other scientist had experimented with transferring disease from one organism to the next in a systematic, scientific manner.

In the 1890s, Ernest Overton, a physiologist (and, incidentally, a cousin of Charles Darwin), immersed a variety of cells in hundreds of solutions containing various substances. Chemicals soluble in oil tended to enter the cell, he noted, while those insoluble in oil could not get in. The cell membrane must be an oily layer, Overton concluded, although he could not quite explain how a substance such as an ion or sugar, insoluble in fats, might enter or leave the cell.

You might encounter yet another macromolecular structure, this one shaped like a tubular meat grinder. It is the cell’s trash compactor, the proteasome, where proteins go to die. Proteasomes degrade proteins into their constituents and eject the chewed-up pieces back into the protoplasm, completing the cycle of synthesis and breakdown.

The Indian tika practitioners had likely learned it from Arabic physicians who, in turn, had learned it from the Chinese. As early as AD 900, medical healers in China had realized that people who survived smallpox did not catch the illness again, thus making them ideal caregivers for those suffering from the disease. A prior bout with an illness somehow protected the body from future instances of that illness, as if it retained a “memory” of the initial exposure. To harness this idea, Chinese doctors harvested a smallpox scab from a patient, ground it into a dry, fine powder, and used a long silver pipe to insufflate it through a child’s nose. Vaccination was a tightrope walk: if the powder contained too much inoculum of live virus, the child would acquire not immunity but the disease—a devastating outcome that occurred about one in a hundred times. But if the child survived the inoculum and its “fester,” he or she would develop merely an attenuated, local disease, with either no symptoms or mild ones, and be immunized for life.

Set in 1762, the story, perhaps apocryphal, has it that an apothecary’s apprentice named Edward Jenner heard a dairy girl say, “I shall never have smallpox, for I have had cowpox. I shall never have an ugly, pockmarked face.” Perhaps he had overheard it from local folklore, for a “milkmaid’s milky skin” was a recurrent English meme. In May 1796, Jenner proposed a safer approach to smallpox vaccination. Cowpox, a virus related to smallpox, caused a far less severe form of the disease, with no deep pustules and no risk of death.

Banting was intrigued. The function of the islands of cells was unknown; perhaps they had some relationship with diabetes. A disease of sugar metabolism—when the body cannot sense or adequately signal the presence of sugar, causing sugar to build up in blood and spill out in urine—diabetes was a mystifying illness.

Karl Popper, the eminent historian of science, once recounted the story of a man in the Stone Age asked to imagine the invention of the wheel in some distant future. “Describe what this invention will look like,” his friend asks. The man struggles to find words. “It’ll be round and solid, like a disk,” he says. “It will have spokes and a hub. Oh, and an axle to connect it to the other wheel, also a disk.” And then the man pauses to reconsider what he’s done. In anticipating the invention of the wheel, he has already invented it.

In Silicon Valley, not far from Stanford’s hospital where children with leukemia await transplants to generate new blood, a start-up called Ambrosia is offering transfusions of matched young blood plasma “harvested from youths between sixteen and twenty-five years old” to supposedly rejuvenate the creaking, but very wealthy, shriveling bodies of aging billionaires. Rather than draining old blood from the dead, you infuse young blood into the aged—embalmment in reverse (I am tempted to draw an analogy to vampirism, but perhaps we will find a new euphemism for this chilling kind of attempted cellular rejuvenation—“rebalming,” or “demummification”). One liter of “young blood” costs $8,000; two liters is a bargain at $12,000. In 2019, the FDA issued a stern cautionary note against the program, citing lack of benefit, although Ambrosia argues that the therapy works.

Nestled at the center of each of the proteins is another chemical: heme. And at the center of heme sits an atom of iron. It is a doll-within-a-doll-within-a-doll scheme. Red blood cells contain hemoglobin molecules that contain heme that, in turn, clasps iron atoms. It’s the iron that binds and unbinds the oxygen. The elaborate apparatus built around those four iron atoms in the hemoglobin molecule has a distinct molecular purpose. Red blood cells cannot simply bind oxygen and hold on to it; they have to release it. The red cells pick their payload—oxygen—from the capillaries of the lung and ferry it around. And when the cells reach oxygen-poor environments in the body—with the heart muscle pumping and pushing them around minute after minute—hemoglobin, literally, twists and unclasps the oxygen that the iron atoms have bound. Hemoglobin is blood’s hidden secret—a complex of proteins so vital to our existence as organisms that we have evolved a cell whose principal job is to act as a suitcase to carry it around.