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

by Siddhartha Mukherjee

In the 1940s, this wing of the immune response—neutrophils, macrophages, among other cell types, with their attendant signals and chemokines—began to be termed the “innate immune system.”II Innate, in part, because it exists inherently in us, with no requirement to adapt to, or learn, any aspect of the microbe that caused the infection.

The antibody-making cells were called B cells, after the word bursa. Mammals, including humans, don’t have a cloacal bursa. Our bodies produce B cells primarily in the bone marrow (thankfully, another B), which then mature in the lymph nodes.

Inner worlds, outer worlds, separated by membranes. What do T cells do during an infection? Imagine, as a human immune system might see it, that there are two pathological worlds of microbes. There is an “outer” world of a bacterium or a virus floating outside the cell, in lymph fluid or blood, or in tissues. And there is an “inner” world of a virus that is embedded and living within a cell. It is the latter world that presents a metaphysical, or rather a physical, problem. A cell, we said before, is a bounded, autonomous entity with a membrane that seals it from the outside. Its inside—the cytoplasm, the nucleus—is a closed sanctum, largely inscrutable from the outside, except for the signals, or receptors, that the cell chooses to send to its surface.

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.

There is a duality in the immune system: one recognition system needs no cellular context (B cells and antibodies), while the other is triggered only when the foreign protein is presented in the context of a cell (T cells). It’s this duality that ensures that viruses and bacteria are not just cleared from the blood by antibodies but are also cleared from infected cells where they could otherwise be harbored safely, by T cells.

What is the self? An organism, as I suggested before, is a cooperative union of units; a parliament of cells. But where does the union begin and end? What if a foreign cell tried to join the union? What passport must it carry that enables it to pass?

Long before the birth of cell biology, Aristotle imagined the self as the core of being; a unity of the body and the soul. The physical boundary of the self, he proposed, was defined by the body and its anatomy. But the totality of the self was a unity of that physical vessel with a metaphysical entity that occupied it—the body filled by the soul.

Immunologists called the self-reactive cells “forbidden clones”—forbidden because they had dared to react to some aspect of a self peptide and were therefore deleted from existence before they could be allowed to mature and attack the self. Burnet likened them to “holes” in immune reactivity. 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 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. Sometime in the future, we will understand why evolution chose to pair these cells. But the regulatory T cell remains a mystery—a cell that looks like it might activate immunity, but actually suppresses it.

The coordinated pulsation of the heart’s cells fascinated physiologists. In the 1880s, German biologist Friedrich Bidder had noted that the cells of the heart “branch and intercommunicate, forming a continuum.” They form a consortium of sorts—a citizenry of cells. The source of their contractile power seemed to lie in their togetherness, their belonging.

“In order to make a system which can shorten,” he wrote, “Nature has to use thin and long protein particles.” By then, one of the “thin and long proteins” had already been identified. He wrote: “The threadlike, very thin and long protein particles out of which Nature has built the contractile matter is ‘myosin.’ ”

The Brain—is wider than the Sky— For—put them side by side— The one the other will contain With ease—and you—beside— The Brain is deeper than the sea— For—hold them—Blue to Blue— The one the other will absorb— As sponges—Buckets—do— —Emily Dickinson, c. 1862

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.

Depression is a flaw in love. But more fundamentally, perhaps, it is also a flaw in how neurons respond—slowly—to neurotransmitters. It is not just a wiring problem, Greengard believes, but rather a cellular disorder—of a signal, instigated by neurotransmitters, that somehow malfunctions and creates a dysfunctional state in a neuron. It is a flaw in our cells that becomes a flaw in love.

Type 1 diabetes, which affects several million patients around the globe, is a disease in which immune cells attack the beta-islet cells of the pancreas. Without insulin, the body cannot sense the presence of sugar—even if there is enough of the chemical in the blood. The cells in the body, imagining that the body has no sugar, begin to scramble around for other forms of fuel. The sugar, meanwhile, all readied up but with nowhere to go, spikes threateningly in the blood, and spills into the urine. Sugar, sugar everywhere—but not a molecule in cells to satiate them. 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 liver, pancreas, brain, and kidney are four of the principal organs of homeostasis.II The pancreatic beta cells control metabolic homeostasis through the hormone insulin. The kidneys’ nephrons control salt and water, maintaining a constant level of salinity in the blood. The liver, among many of its functions, prevents us from being soused in toxic products, including ethanol. The brain coordinates this activity by sensing levels, sending out hormones, and acting as a master orchestrator of balance-restoration.

“He not busy being born is busy dying” […] You are busy being born the whole first long ascent of life, and then, after some apex, you are busy dying: that’s the logic of the line.

It is the acrobatic balance between self-preservation and selflessness—self-renewal and differentiation—that makes the stem cell indispensable for an organism, and thereby enables the homeostasis of tissues such as blood.

hundreds of labs have started working on iPS cells. The allure is this: you take your own cell—a skin fibroblast, or a cell from your blood—and you make it crawl backward in time and transform it into an iPS cell. And from that iPS cell, you can now make any cell you’d like—cartilage, neurons, T cells, pancreatic beta cells—and they’d still be your own. There would be no problem with histocompatibility. No immune suppression. No reason to worry about the guest turning immunologically against the host. And in principle, you could repeat the process infinitely—iPS into beta cell back to iPS cell into beta cell (to be fair, no one has tried this yet). The recursiveness, though, sets up yet another fantasy of a new human: one in whom every degenerated organ, or tissue, could be regenerated, and regenerated again, ad infinitum.

Injury and repair share a border—except, as we age, injury, and the weariness of regenerative capacity, keeps infiltrating, creeping over the hedge. Osteoarthritis is a degenerative disease that arises from a regenerative disease. It is a flaw in rejuvenative homeostasis.

In some organs, injury overwhelms repair. In some organs, repair keeps apace with injury. In yet other organs, there’s a delicate equilibrium between one rate and another. The body, in its steady state, seems to be maintained—suspended—in constancy. Don’t just do something, stand there. But standing there, standing still, is not a statis but a frenetically active process. What appears as “stillness”—stasis—is, in fact, a dynamic war between these two competing rates. “At death you break up,” Philip Larkin wrote, “the bits that were you / Start speeding away from each other for ever / With no one to see.”

But death isn’t a flying apart of organs. It is the withering grind of injury set against the ecstasy of healing. Tenderness, as Ryan puts it, combatting rot. The central corporals in this pitched battle are cells—cells dying in tissues and organs, and cells regenerating tissues and organs. Return, for a moment, to the notion of homeostasis—the maintenance of a constancy in the internal milieu. We first evoked this idea to understand how the cell maintains its internal fixity. We then used it to understand how a healthy body adjusts to metabolic and environmental changes—salt load, waste disposal, sugar metabolism. We apply it, now, to the maintenance of balance between injury and repair. Death—the most absolute of absolutes—is, in fact, a relative balance between forces of decay and rejuvenation. If you tip the balance in one direction—when the rate of injury overwhelms the rate of recovery or regeneration, you fall off the edge. The osprey, buffeted by the changing winds, cannot remain suspended in midair. I

But cancer is, in a sense, a disorder of internal homeostasis: its hallmark is that cell division is dysregulated. The genes that control these accelerators and brakes are broken—i.e., mutated—such that proteins that they encode, the regulators of cell division, no longer function in their appropriate contexts. The accelerators are permanently jammed, or the brakes fail permanently. More typically, it is a combination of both events—jammed accelerator genes and snapped brakes—that drives the dysfunctional growth of a cancer cell. The cars speed through the traffic jam, piling up on each other and causing tumors. Or they frantically move into alternate routes, causing metastasis. I don’t mean to give cancer cells personalities. 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.

One astonishing feature of cancer is that any individual specimen of cancer has a permutation of mutations that is unique to

Recall that unicellular organisms evolved into multicellular organisms—not once, but many independent times. The driving forces that goaded that evolution, we think, were the capacity to escape predation, the ability to compete more effectively for scarce resources, and to conserve energy by specialization and diversification. Unitary blocks—cells—found mechanisms to achieve this specialization and diversification by combining common programs (metabolism, protein synthesis, waste disposal) with specialized programs (contractility in the case of muscle cells, or insulin-secreting capacity in pancreatic beta cells). Cells coalesced, repurposed, diversified—and conquered.