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.

Schleiden and Schwann weren’t the first to see cells, or to realize that cells were the fundamental units of living organisms. The acuity of their insight was in the proposition that a deep unity of organization and function ran through living beings. “A bond of union” connects the different branches of life, Schwann wrote.

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.

Humans were ecosystems of these living units. We were pixelated assemblages, composites, our existence the result of a cooperative agglomeration. We were a sum of parts.

The transformation of medicine made possible by our new understanding of cell biology can be broadly divided into four categories. The first is the use of drugs, chemical substances, or physical stimulation to alter the properties of cells—their interactions with one another, their intercommunication, and their behavior. Antibiotics against germs, chemotherapy and immunotherapy for cancer, and the stimulation of neurons with electrodes to modulate nerve cell circuits in the brain fall in this first category. The second is the transfer of cells from body to body (including back into our own bodies), exemplified by blood transfusions, bone marrow transplantation, and in vitro fertilization (IVF). The third is the use of cells to synthesize a substance—insulin or antibodies—that produces a therapeutic effect on an illness. And most recently, there is a fourth category: the genetic modification of cells, followed by transplantation, to create cells, organs, and bodies endowed with new properties.

In 1922, a fourteen-year-old boy with type 1 diabetes was resuscitated from a coma—born anew, as it were—by the infusion of insulin extracted from the pancreatic cells of a dog. 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.

“Every theory, hypothesis, or point of view adopts life’s definitions in accordance with its own scientific interests and premises. There are hundreds of working, conventional definitions of life within scientific discourse, but none has been able to achieve a consensus.”

Life’s definition, as it stands now, is akin to a menu. It is not one thing but a series of things, a set of behaviors, a series of processes, not a single property. To be living, an organism must have the capacity to reproduce, to grow, to metabolize, to adapt to stimuli, and to maintain its internal milieu.

one might define life as having cells, and cells as having life.

we need to understand cells to understand the human body. We need them to understand medicine. But most essentially, we need the story of the cell to tell the story of life and of our selves.

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

A cell enlivens genes.

cell uses this set of proteins (and the biochemical products made by proteins) in conjunction with one another to start coordinating its function, its behavior (movement, metabolism, signaling, delivering nutrients to other cells, surveying for foreign objects), to achieve the properties of life. And that behavior, in turn, manifests as the behavior of the organism.

The metabolism of an organism reposes in the metabolism of the cell. The reproduction of an organism reposes in the reproduction of a cell. The repair, survival, and death of an organism repose in the repair, survival, and death of cells. The behavior of an organ, or an organism, reposes in the behavior of a cell. The life of an organism reposes in the life of a cell.

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, ...

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

In 1543, he published his anatomical works in seven volumes entitled De Humani Corporis Fabrica (The Fabric of the Human Body). The word Fabric in the title was a clue to its texture and purpose: this was the human body treated like physical material, not mystery; made of fabric, not spirit. It was part medical textbook, with nearly seven hundred illustrations, and part scientific treatise, with maps and diagrams that would lay the foundation for human anatomical studies for centuries to come.

During the sixteenth and seventeenth centuries, most diseases were attributed to miasmas: poisonous vapors emanating from sewage or contaminated air. 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.”)

And although Bichat was occasionally wrong about the structures of some of these elementary tissues, he moved cell biology toward histology: the study of tissues, and of systems of cooperating cells.

More than any microscopist, though, it was François-Vincent Raspail who tried to build a theory of cellular physiology out of these early observations. Yes, there were cells, cells everywhere, he acknowledged—in plant and animal tissues—but to understand why they existed, they must be doing something.

Raspail formulated the Latin aphorism Omnis cellula e cellula: “From cells come cells.”

natural corollary of vitalism was the notion of “spontaneous generation”: that this vital fluid pervading all living systems was necessary and sufficient to create life out of its own. Including cells.

Vitalists continued to claim that cells coalesced out of the vital fluids. To prove them wrong, non-vitalists would have to find a way to explain how cells arose—a challenge, vitalists believed, that could never be met.

The second debate that simmered through the early 1800s was preformation: the idea that the human fetus was already fully formed, albeit miniaturized, when it first appeared in the womb following fertilization.

was the demolition of the theories of vitalism and preformation—and their displacement by cell theory—that would firmly establish the new science and usher in the century of the cell.

Neither Schwann nor Schleiden had found something new or unveiled an undiscovered property of the cell. It wasn’t novelty that brought them fame; it was the sheer brazenness of their claim. They collated the work of their predecessors—Hooke, Leeuwenhoek, Raspail, Bichat, and a Dutch physician-scientist named Jan Swammerdam—and synthesized it into a radical proposition.

All living organisms are composed of one or more cells. The cell is the basic unit of structure and organization in organisms.

The division of one cell gave rise to two, and two to four, and so forth. “Omnis cellula e cellula,” he wrote—“from cells come cells.” Raspail’s phrase had become Virchow’s central tenet.

Cellular Pathology detonated through the world of medicine. Generations of anatomic pathologists had thought about diseases as the breakdown of tissues, organs, and organ systems. Virchow argued that they had missed the real source of the illness. Since cells were the unit blocks of life and physiology, Virchow reasoned, then the pathological changes observed in diseased tissues and organs should be traced back to pathological changes in the units of the affected tissue—in other words, to cells. To understand pathology, doctors needed to look for essential disruptions not just in visible organs but in the organ’s invisible units.IV

(“All living organisms are composed of one or more cells,” and “The cell is the basic unit of structure and organization in organisms”): 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.

“Life is, in general, cell activity. Beginning with the use of the microscope in the study of the organic world, far-reaching studies […] have shown that all plants and animals are, in the beginning […] a cell within which other cells develop to give rise again to new cells that together, undergo transformation to new forms, and, finally… constitute the amazing organism.”

“Every disease depends on an alteration of a larger or smaller number of cellular units in the living body, every pathological disturbance, every therapeutic effect, finds its ultimate explanation only when it’s possible to designate the specific living cellular elements involved.”

was germ theory—that microbes are independent, living cells capable, in some cases, of causing human illnesses—that would first bring the cell (in this case, the microbial cell) into intimate contact with pathology and medicine.

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.

(1) the organism/microbial cell must be found in a diseased individual, not in a healthy individual; (2) the microbial cell must be isolated and cultured from the diseased individual; (3) the inoculation of a healthy individual with the cultured microbe must recapitulate the essential features of the disease; and (4) the microbe must be re-isolated from the inoculated individual and match the original microorganism.I

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.

the 1850s, not long after Semmelweis had been dismissed to Budapest, an English physician named John Snow was tracking the course of a raging cholera epidemic in the Soho area of London.

Even in ancient India and Egypt, physicians cleaned their instruments by boiling them. Yet in Lister’s time, surgeons paid little attention to the possibility of contamination by microbes. Surgery was an unfathomably unsanitary practice, as if designed intentionally to defy any historical knowledge of hygiene.

In 1910, the first among these, an arsenic derivative known as arsphenamine, was discovered by Drs. Paul Ehrlich and Sahachiro Hata, who found it could kill syphilis-causing microbes. Soon there was a seemingly limitless bounty of antibiotics, among them penicillin, an antibacterial chemical secreted by a fungus that was discovered in molding plates by Alexander Fleming in 1928, and the anti-TB drug streptomycin, isolated from bacteria in clods of dirt by Albert Schatz and Selman Waksman in 1943.

Every potent antibiotic—doxycycline, rifampin, levofloxacin—recognizes some molecular component of human cells that is different from a bacterial cell. In this sense, every antibiotic is a “cellular medicine”—a drug that relies on the distinctions between a microbial cell and a human cell. The more we learn about cell biology, the subtler distinctions we uncover, and the more potent antimicrobials we can learn to create.

(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.)

The word eukaryote is a technicality: it refers to the idea that our cells, and the cells of animals, fungi, and plants, contain a special structure called a nucleus (karyon, or “kernel,” in Greek). This nucleus, as we will soon learn, is a storage site for chromosomes. Bacteria lack nuclei and are called prokaryotes—that is, “before nuclei.” Compared with bacteria, we are fragile, feeble, finicky beings capable of inhabiting vastly more limited environments and restricted ecological niches.

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.

Nick Lane, the evolutionary biologist at University College London, puts it in his book The Vital Question: Energy, Evolution, and the Origins of Complex Life,

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.”

A cell is not a blob of chemicals; it has distinct structures, or subunits, within it that allow it to function independently. The subunits are designed to supply energy, discard waste, store nutrients, sequester toxic products, and maintain the internal milieu of a cell. Second, a cell is designed to reproduce, so that one cell can produce all the other cells that populate the organism’s body. And finally, for multicellular organisms, the cell (or at least the first cell) is designed to differentiate and develop into other specialized cells, so that various parts of the body—tissues, organs, organ systems—can be formed.

“The cell,” Rudolf Virchow proposed in 1852, “is a closed unit of life that bears within itself […] the laws governing its existence.” To begin with, a bounded, autonomous living unit—a “closed unit” that bears the laws that govern its existence—must have a boundary.

imagine entering and exploring the interior of a cell as an astronaut might imagine exploring an unfamiliar spacecraft. From far away, you might see the spacecraft’s/cell’s outer contours: the oblong, gray-white sphere of an oocyte, or the crimson disk of a red blood cell. As you approach the cell membrane, you might begin to see its outer layer more clearly. Bobbing on that fluid surface are proteins. Some might be receptors for signals, while others might function like molecular glue for attaching one cell to another. Some of these might be channels. If you are fortunate, you might watch a nutrient or an ion slip through the pore and into the cell. And now, you, too, might “board” the craft. You would dive through the hull—that is, into the bilayer membrane, moving rapidly through the space between the two layers, only about ten nanometers thick, or ten thousand times thinner than a strand of human hair—and emerge inside. Look around and above: now the inner lamella of the cell membrane would hang above you like the fluid surface of the ocean as seen from below. You would also see the inner parts of the proteins dangling above you, like the underbellies of buoys.

The cytoskeleton tethers components of the cell together, and is required for the movement of the cell. When a white blood cell creeps toward a microbe, it uses actin filaments, among other proteins, to push its feelers forward—gelling and un-gelling its front like the ectoplasmic movement of an alien.

Building proteins is one of the cell’s major tasks. Proteins form enzymes that control the chemical reactions of life. They create structural components of the cell. They are the receptors for signals from the outside. They form pores and channels across the membrane, and the regulators that switch genes on and off in response to stimuli. Proteins are the workhorses of the cell.