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

by Siddhartha Mukherjee

The Nobel is not awarded posthumously, but the decision to award Steinman the prize had been made long before his death, and so the honor was still conferred on him).

In quite the opposite sense, some Vedic philosophers in India, writing between the fifth and second century BC, welcomed the erasure of the individual self and its fusion with the universal. They rejected the Greek dualism between the body and the soul—and, indeed, between an individual body and the cosmic soul.

But the regulatory T cell remains a mystery—a cell that looks like it might activate immunity, but actually suppresses it.

Lupus is a slippery, motile disease. It might affect just one organ system, such as the skin or the kidneys, or it might suddenly go after multiple systems at once.

Autoimmunity, the attack on self cells, generated an obvious question: What if the immunological toxicity could be turned on cancer cells?

Cancers, varied as they are, share some common features—among them, their invisibility to the immune system.

But what, exactly, were cancer cells doing to achieve invisibility? Might the cells be using the same mechanisms that the normal body uses to prevent attacks on itself—that is, activating the trigger-lock systems that prevent autoimmunity?

The pathogenicity of SARS-COV2, in short, perhaps lay precisely in its ability to dupe cells into believing that it is not pathogenic.

Pandemics teach us about epidemiology. But they also teach us about epistemology: how we know what we know.

Covid exposed the humility that is required to cohabitate with these characters surrounding us. We are like Dickens, except encircled by shadows, ghosts, and liars. As one physician told me: “We don’t even know what we don’t know.”

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

What I felt wasn’t writer’s block, but writer’s languish: I wrote, yes, but everything that I put on the page seemed to lack life and energy.

The pituitary gland—one of the few unpaired glands in the body, dangled, like a tiny berry, from the middle.

The pineal gland, which Descartes thought was the seat of the soul, was also nestled in the center.

In 1873, Camillo Golgi, the Italian biologist working in Pavia, found that if he added a solution of silver nitrate to a slice of translucent neuronal tissue, a chemical reaction occurred, resulting in a black stain that accumulated within some of the neurons.

The process of nervous conduction, then, was the movement of the impulse from cell to cell. There wasn’t a single, reticular spiderweb of “cellular appendages,” as Golgi had proposed, or a syncytium of citizen cells, as in the heart. Rather, nerve cells “chattered” with each other—collecting inputs (via dendrites) and generating outputs (via the axon). And it was this cellular chatter—or rather, intercellular chatter—that gave rise to the profound properties of the nervous system: sentience, sensation, consciousness, memory, thinking, and feeling.

“It takes a courageous person,” the poet Kay Ryan once wrote, “to leave spaces empty”—and Cajal, the draftsman-scientist, was anything but timorous. That space—about twenty to forty nanometers in distance—is left blank.

But like the negative space in a Chinese painting, that space might represent the most important element of the whole drawing—and arguably, of the entire physiology of the nervous system.

It might be useful to distinguish two broad kinds of problems in science. The first kind—call it the “eye in the sandstorm” problem—arises when there’s such immense confusion in a field that no pattern or road map is visible.

Graz, Austria, another neurophysiologist, Otto Loewi, also converged on the idea of chemical neurotransmitters. The night before Easter Sunday, 1920—in the brief lull of peace between the wars—he dreamed of an experiment.

The reasons for this paring back of synapses is a mystery, but synaptic pruning is thought to sharpen and reinforce the “correct” synapses, while removing the weak and unnecessary ones. “It reinforces an old intuition,” a psychiatrist in Boston told me. “The secret of learning is the systematic elimination of excess. We grow, mostly, by dying.” We are hardwired not to be hardwired, and this anatomical plasticity may be the key to the plasticity of our minds.

Microglia have evolved to “eat” pieces of our own brain.

Recent experiments suggest that dysfunctions in glial pruning may be related to schizophrenia—a disease where the pruning doesn’t occur appropriately.

Things got worse. I dealt with it by ignoring it, until it had crested fully.

Our conversations ranged widely. Neuroscience, cell biology, university gossip, politics, friendships, the latest exhibition at the Museum of Modern Art, the newest findings in cancer research; Paul was interested in everything.

We might, then, divide the pathologies of the brain into those that affect the “fast” signals (the rapid electrical conduction of neuronal cells), those that affect “slow” signals (the biochemical cascades that are altered in nerve cells), and those that fall somewhere in between.

“Depression is a slow brain problem,”

not move on. Andrew Solomon, the writer, once described depression as a “flaw in love.” But in medical terms, it was a problem with the regulation of neurotransmitters and their signals. A flaw in chemicals.

“It’s not just the level of serotonin,” Paul said emphatically, jabbing his fingers in the air. The New York air was clear and bitingly cold, and his breath left a drifting trail of mist behind him. “That’s way too simple. It’s what serotonin does to the neuron. The way it changes the neuron’s chemistry, and its metabolism,” he said. “And that might vary from one individual to the next.”

Heart cells are so physically conjoined that an electrical impulse within one spreads to the other through junctions between the cells. There are lots of murmurs, but very few shouts.

There must be a means for one part of the body to “meet” a distant part of a body. We call these signals “hormones,” from the Greek hormon—to impel, or to set some action into motion. In a sense, they impel the body to act as a whole.

The discovery of insulin is now widely attributed to Banting and Best.

It is one of the defining metabolic crises of the human body—cellular starvation in the presence of plenty.

We think of metabolism as a mechanism to generate energy. But flip it around, and it’s also a mechanism to generate waste. The kidney dispenses some of this, as above, through urine. But the kidney is not a detoxifying plant: its master plan for waste is to merely wash it away down a sewer. Liver cells, in contrast, have evolved dozens of mechanisms to detoxify and dispense waste.

One of the remaining mysteries of cell biology is why, in adulthood, some organs can repair, and some rejuvenate, while others lose both capacities.

Simplified to its essence, flow cytometry is like coloring cells with crayons—each cell a different permutations of colors (one: blue and green; another: green and red) based on the permutations of proteins on their surface. The “crayons” are antibodies, carrying chemicals that fluoresce in different colors, that recognize the different proteins on the surface of a cell. A machine can be used to separate cells based on their staining by different permutations of colors.

In 1958, the French pioneer of bone marrow transplantation, Georges Mathé, had transplanted bone marrow from a series of donors to some Yugoslavian researchers who had accidentally received toxic doses of radiation and had thereby developed fulminant bone marrow failure.

The nurse ran her hands along the smooth line of the curve and smiled. I thought of Grishchenko in his helicopter, suspended in midair and surrounded by a fog of toxic plutonium. Of the boy who went into a cave to kill a bear. I could sense the terrifying fear of the young child in the cement chamber, bent over with nausea, while the dogs barked next door. I thought of the nurses with wet towels, and of those who stayed overnight, those who kept vigil against infections, those who held the patients’ hands all day, and watched them as if they were their own children. As the nurses left the hospital, many of the doctors and the staff stood up as they passed. It was a silent recognition of their many, many contributions. I realized that I had tears in my eyes. Cell therapy for blood diseases had a terrifying birth.

Stem cells have been found in diverse organs, and in diverse organisms. But more than any other type of stem cell, the two that remain the most fascinating, and most controversial, perhaps, are the embryonic stem cell (ES cell) and its even stranger cousin, the induced pluripotent stem cell (iPS cell).

Elucidating the mechanisms that control differentiation will facilitate the efficient, directed differentiation of ES cells to specific cell types. The standardized production of large, purified populations of […] human cells such as cardiomyocytes and neurons will provide a potentially limitless source of cells for drug discovery and transplantation therapies. Many diseases, such as Parkinson’s disease and juvenile-onset diabetes mellitus, result from the death or dysfunction of just one or a few cell types.

The result was an utter shock to biologists—a Loma Prieta that shook the Earth plates of the stem cell world. I remember a senior chemical biologist from my department returning from a seminar in Toronto where Yamanaka had just presented his data visibly ruffled, breathless with disbelief. “I just cannot believe it,” he told me after he’d returned from the talk. “But the result has been reproduced over and over again. It’s got to be true.” Yamanaka had made a stem cell out of a fibroblast—a transition thought to be impossible in biology. It was as if—presto!—he had turned biological time backward. He had changed a fully grown adult not just into a baby, but into an embryo.

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?

Osteoarthritis was the forme fruste—the frustrated form—of a tissue trying to repair itself, but failing.

Osteoarthritis is a degenerative disease that arises from a regenerative disease. It is a flaw in rejuvenative homeostasis.

This is a Darwinian process, requiring natural selection: the cells that succeed are the fittest for survival. They are naturally selected to be the cells most adapted to grow and divide, in circumstances where they do not belong, and in tissues where they do not belong. Natural selection creates cells that disobey every law of belonging, except for the laws that they have created for themselves.

They break the laws of cellular civility, of citizenship.

But Smithers—pushing provocation, to be sure—was trying to focus attention away from the cancer cell to the behaviors of these cells in their real environments.

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.

department.) The talk was a provocation. Sandel challenged the human quest for enhancement, basing his argument, ultimately, on what the late theologian William May called “an openness to the unbidded.”

He thinks he has found it in the idea of giftedness. To some degree, being a good parent, athlete or performer is about accepting and cherishing the raw material you’ve been given to work with