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

by Siddhartha Mukherjee

original inoculum. But beyond vaccines, the discovery of antibodies reignited Paul Ehrlich’s fantasy of a magic bullet: if an antibody could somehow be persuaded to attack a cancer cell or a microbial pathogen, it would work as a natural drug against the cell. It would be a medicine like none other: a drug tailor-made to attack and kill its target.

The problem was that single plasma cells were not immortal. They would grow for a few days, then struggle to stay alive, and finally shrivel and die. Milstein, working with the German cell biologist Georges Köhler, came up with a solution that was as brilliant as it was unorthodox: using a virus that could glue cells together, they fused the B cell with a cancer cell. I am still awestruck by the idea. How did they even think of using the undead to resuscitate the dying? The result was one of the strangest cells in biology. The plasma cell retained its antibody-secreting property, while the cancer cell conferred its immortality.

It is a testament to the infancy of cell biology as a science that the physiology of one of the most essential cells of the human body remained a mystery as late as the 1970s. T cells were discovered only about fifty years ago. And it was barely two decades after Miller’s experiment—in 1981—that these cells would become the epicenter of one of the defining epidemics in human history.

what if a virus has taken residence within a cell? What about, say, a flu virus that has infiltrated the cell and hijacked its protein-making apparatus in order to churn out viral proteins that are indistinguishable from the cell’s own? This is what viruses do: they “go native.” A flu virus turns its hostage into a veritable flu factory, producing thousands of virions per hour. And because antibodies cannot enter cells, how are they to identify one of these rogue cells masquerading as a normal cell? What, then, prevents any virus from using every cell in our body as a perfect microbial sanctuary? The answers to all these questions, I would soon find out, lay in the cell whose seductive song had tugged me all the way from California to Alain Townsend’s lab at Oxford; the cell that could, with nearly miraculous sensitivity, discern a virus-infected cell from an uninfected one, and the cell that can discriminate the self from the nonself. The subtle, wise, discerning T cell.

your T cells can recognize virally infected cells only if they come from your body, not someone else’s.III

Although a CD8 T cell could recognize a cell from the same body, it killed only infected cells from the same body. No viral infection, no kill. It was as if the T cell was capable of asking two independent questions. First: Does the cell that I am surveying belong to my body? In other words, is it self? And second: Is it infected with a virus or a bacterium? Has the self been changed? Only if both were true—the self and infection—would a T cell kill its target.

In biology, there is rarely a more poignant moment than when a structure of a molecule melds with its function: what a molecule looks like, and what is does, fall into perfect union. Take DNA, the iconic double helix. It looks like an information carrier—a string of four chemicals, A, C, T, and G, with a unique sequence (ACTGGCCTGC) just like a four-letter Morse code.

The sperm’s tail that whips around to make the sperm squirm toward the egg looks like a tail, except that it is built out of an assemblage of proteins. The motor that makes the tail spin resembles a motor, with a set of moving parts arranged in a circle. And the hook that connects the motor to the tail, transforming circular motion to the propeller-like, swimming motion of the sperm, looks like a hook engineered precisely to achieve this transformation.

“Everything came together in that image. Everything clicked,” Alain said. The foreign element (the viral peptide in its groove) and the self element (the spiral MHC edges of the molecule) are both visible to the T cell. Alain was infinitely moved by looking at that structure; he could actually visualize the presentation of a viral peptide to a T cell. “[E]very immunologist’s pulse will race as he or she sees the three-dimensional structure of the binding site of an MHC molecule displayed for the first time,” he wrote in the pages of Nature, because it will explain the “structural basis” of antigen recognition. That image of the class I molecule answered a thousand questions from immunologists and raised a thousand more. Alain titled his 1987 article with a fragment of a poem borrowed from William Butler Yeats: Those images that yet Fresh images beget.

The matching of form and function is one of biology’s most beautiful ideas, first articulated centuries ago by thinkers such as Aristotle.

Our immune system is built on both the recognition of self and of its distortion. It is designed, by evolution, to detect the altered self.

Antigen processing and presentation to CD4 and CD8 cells—the mainstays of T cell recognition—are slow but painstakingly methodical processes. Unlike an antibody, a gunslinging sheriff itching for a showdown with a gang of molecular criminals in the center of town, a T cell is the gumshoe detective going door to door to look for perpetrators hiding inside.

Unlike the B cell, though, the T cell isn’t looking for a culprit to come bursting out of the saloon, guns a-blazing. It is, like some omniscient Sherlock Holmes with a pipe and an umbrella, seeking the portent of a person. The debris left behind by an inner presence. A torn-up letter, with the fragment of a name, discarded in the trash can outside. (You might think of that crumpled piece of stationery, mounted within a trash can, as a peptide presented on an MHC molecule.)

We typically think of AIDS as a viral disease. But it is also equally a cellular disease. The CD4-positive T cell sits at the crossroads of cellular immunity. To call it a “helper” cell is to call Thomas Cromwell a mid-level bureaucrat; the CD4 cell is not so much a helper as it is the master machinator of the entire immune system, the coordinator, the central nexus through which virtually all immune information flows.

The collapse of CD4 cells thus cascades rapidly into a collapse of the immune system in total.

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. They termed the self atman.

The universal, multitudinous self, in contrast, was the Brahman. For these philosophers, the self was an ideal fusion of atman and Brahman, or perhaps more accurately, the seamless flow of the universal self through the individual self.

The phrase “Tat Twam Asi”—“That you are”—permeates the Upanishads and is an expression of the boundless self that permeates not just a single physical body but also the cosmos.

The whole ecosystem of living beings, we might say, is connected through a network of relationships and, to some extent, the erasure of the boundaried self. A human body and a tree, and the bird that dwells in that tree, say, are linked through such networks—networks that ecologists are just beginning to decipher. The bird eats the fruit from a tree and disseminates the seeds through its droppings; the tree, reciprocally, provides a perch for that bird. It’s not invasion, the ecologists insist. It’s interconnectedness.

For cell biologists, though, it is physical fusion that continues to raise a fundamental conundrum. The notion of chimerism—the fusion of physical selves—is not a New Age fantasy but an age-old threat.

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.”

T cells are born in the bone marrow as immature cells and migrate to the thymus to mature.

as Burnet had predicted, they found that the immature T cells that recognized pieces of that protein—the ones that attacked the self—were deleted in the thymus by way of a process called negative selection. The deleted T cells never matured. They left the “holes” that Burnet had proposed in self-reactive T cells.

It is an unsolved quirk of the immune system that the cell type that confers active immunity and incites inflammation (the T cell) and the cell type that dampens these processes (the regulatory T cell) arise from the same parent cells: T cell precursors in the bone marrow. Indeed, aside from very subtle distinctions in genetic markers, T cells and T reg cells are anatomically indistinguishable. And yet they are functionally complimentary. Immunity and its opposite are twinned: the Cain of inflammation conjoined with the Abel of tolerance.

Autoimmunity, the attack on self cells, generated an obvious question: What if the immunological toxicity could be turned on cancer cells? After all, malignant cells occupy the disturbing boundary of the self and the nonself; they are derived from normal cells and share many features of normality, but they are also malignant invaders—rhinoceroses in one perception, and unicorns in another.

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

Harold Varmus, the Nobel-winning cancer biologist, called cancer a “distorted version of our normal selves.” And so they are: the proteins that cancer cells make are, with a few exceptions, the same ones made by normal cells, except cancer cells distort the function of these proteins and hijack the cells toward malignant growth.

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?

If you imagine CTLA4 on T cells as a safety switch on a gun, then PD-L1, on normal cells, is an orange jacket worn by an innocent bystander that says, “Don’t shoot. I’m harmless!”V

The binding of CTLA4 on T cells makes them impotent. The presence of PD-L1 on normal cells makes them invisible. Somewhere in the combination of impotence and invisibility lie the twin mechanisms that prevent the body from swallowing itself. Cancers, we now know, can use both these mechanisms to cloak themselves against immune attack.

A novel form of immunotherapy for cancer, termed “checkpoint inhibition”—the removal of tolerizing checks on T cells—was born.

the Shanghai woman had fallen ill on her flight back to China. She had tested positive for SARS-COV2. But here was the puzzle: she had had no symptoms when she had met him; she had seemed perfectly well. She had only fallen ill two days later. In short, she had transmitted the virus to the man while being presymptomatic. No one could have told her, or the exposed man, that she had been a carrier of the virus. No isolation or quarantine based on symptoms could have stopped the virus. The mystery deepened when the man was tested. His symptoms had defervesced by then; he had returned to work, feeling perfectly well. But when the virus was measured in his sputum, he turned out to be a roiling cauldron of contagion: there were one hundred million infectious viral particles per milliliter of spit; just a few coughs might fill a room with a dense, invisible, deeply contagious fog. He, too, was transmitting virus while experiencing no discernible symptoms.

If one person can infect three, the growth of infections is necessarily exponential. Three, nine, twenty-seven, eighty-one. In twenty cycles, the number reaches 3,486,784,401—about half the population of the globe.

the most severe cases of SARS-COV2 infection, he found, occurred in patients—typically men—who lacked the ability to elicit a functional type 1 interferon signal after infection. At times, cell biology produces the most peculiar and unexpected of results. These men with severe Covid had preexisting auto-antibodies against type 1 interferon—i.e., their bodies had attacked and rendered the protein nonfunctional even before they had been infected. These patients were already deficient in the type I interferon response—but were unaware of their deficiency until the virus struck. For them, Covid infection had unveiled a long-standing, but previously invisible, autoimmune disease—a dormant, unknowable horror autotoxicus (against type 1 interferon, the viral alarm bell) that was only revealed by SARS-COV2 infection.

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

“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 interferon response], you control the virus and have a mild disease. If you don’t, you have uncontrolled virus replication in the lung that […] fuels the fire of inflammation leading to severe disease.” Iwasaki used a particularly vivid phrase to describe this kind of hyperactive, dysfunctional inflammation: she called it “immunological misfiring.”

Why does the virus cause more severe disease in men than in women? Again, there are hypothetical answers, but we lack definitive ones. Why do some people generate potent neutralizing antibodies after infection, while others don’t? Why do some suffer long-term consequences of the infection, including chronic fatigue, dizziness, “brain fog,” hair loss, and breathlessness, among a host of other symptoms? We don’t know.

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.

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.

Blood, which we encountered as a model of cellular cooperation and communication, is not a simple “organ.” It is, rather, a system of organs: one to deliver oxygen (red cells), and another to respond to injury (platelets), and yet another to respond to infections and inflammation.

In biology, an “organ” is defined as a structural or anatomic unit, in which cells come together to serve a common purpose. In smaller animals, even a small collection of cells will serve the purpose.

The cells in organs, as we shall see, still utilize the basic principles of cell biology—protein synthesis, metabolism, waste disposal, autonomy. But each cell in each organ is also a specialist: it acquires a unique function that serves the organ as a whole, and ultimately coordinates some aspect of human physiology.

Contemplate the heartbeat: this phenomenon that many of us might consider the epitome of the everyday—the heart will beat more than two billion times over an average person’s life—is, in fact, a miraculously complex feat of cell biology. The heart is a model of cellular cooperation, citizenship, and belonging.

Round and round in circles. “The concept of a circuit of blood does not destroy, but rather advances […] medicine,” Harvey wrote.

But to imagine the heart mechanically, as a pump, is to forget the central conundrum: How do you make a pump out of cells? A pump is, after all, a highly coordinated machine. It needs a signal to dilate and a signal to compress. It needs valves to ensure that the fluid doesn’t flow backward. It requires a mechanism to ensure that the contracting bladder doesn’t wobble without purpose or direction. An uncoordinated pump is no better than a wobbling balloon.

Alexis Carrel, a French scientist at the Rockefeller Institute in New York, cut a small fragment of the heart of an eighteen-day old chick fetus and grew it in liquid culture. “[T]he fragment pulsated regularly for a few days and grew extensively,” he noted. “After the first washing […] the culture grew again very extensively.” When he removed and recultivated a piece of it, he found it still capable of pulsating: in March, nearly three months after having removed it from the chick’s heart, “it was [still] pulsating at a rate that varied between 60 and 84 per minute […].” Ultimately, “on March 12 the pulsations were irregular, and the fragment beat for a series of 3 to 4 p...

it also signaled an equally important idea: the cells of the heart, cultivated outside the body, had the autonomous capacity to pulsate rhythmically

How was its pumping force generated? Szent-Györgyi began with Virchow’s idea: if an organ is capable of contracting and dilating, then its cells must be capable of contraction and dilation. Sitting within each muscle cell, Szent-Györgyi mused, must be some specialized molecule, or set of molecules, that was capable of generating a directional force, thereby shortening the cell—contracting it.

The trick to a muscle cell’s contraction is that these two fibers—actin and myosin—slide against each other, like two networks of ropes. When a cell is stimulated to contract, a part of the myosin fiber binds to a site on the actin fiber, like a hand from one rope gasping the other. It then unclutches it and reaches forward to bind to the next site—a man suspended on one rope, grasping and pulling on the other, one fist upon the next. Clutch. Pull. Release. Clutch. Pull. Release.

heart cells are connected to each other through minuscule molecular channels, called gap junctions. In other words, every cell is inherently designed to communicate with the next. Although many, they behave as one. When a stimulus to contract is generated in one cell, it automatically travels to the next cell, resulting in its stimulation, and ultimately resulting in contraction in unison.