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October 26, 2022 - February 5, 2023
In April 2020, on a sweltering morning in Kolkata, India—the hawks outside my hotel room were circling upward, lifted by the warming air currents—I visited a shrine to the goddess Shitala, the deity that presides over the healing of smallpox. She shares the shrine with Manasa, the goddess of snakes, the healer of poisonous bites and the protectress against venom. Shitala’s name means the “cool one”: the myth runs that she arose from the cooled ashes of a sacrificial fire. But the heat that she is supposed to diffuse is not just the intractable wrath of summer that hits the city in mid-June but
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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
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Variolation had one further legacy: it gave rise to perhaps the first time the word immunity was used. In 1775, a Dutch diplomat who dabbled in medicine, Gerard van Swieten, used the word immunitas to describe the fever and smallpox resistance induced by variolization. The history of immunity, and of smallpox, were therefore to be forever intertwined.
fact, the word vaccine carries the memory of Jenner’s experiment: it is derived from vacca, Latin for “cow.”
Vaccination, more than any other form of medical intervention—more than antibiotics, or heart surgery, or any new drug—changed the face of human health. (A close contender might be safe childbirth.) Today there are vaccines against the deadliest of human pathogens: diphtheria, tetanus, mumps, measles, rubella. Vaccines have been devised to prevent infection by human papillomavirus (HPV), by far the major cause of cervical cancer. And we will soon encounter the triumphal discovery of not just one but several independent vaccines against SARS-COV2, the virus that released the Covid pandemic.
the story of vaccination is not the story of progressive scientific rationalism. Its hero is not Addison, who first found white blood cells. Nor is it Metchnikoff, whose discovery of phagocytes might have opened a door on protective immunity. Not even the scientists who discovered the innate response to bacterial cells merit being lauded as the heroes behind this medical milestone.III Rather, its history is one of veiled hearsay, gossip, and myth. Its heroes are nameless: the Chinese doctors who air-dried the first pox pustules; the mysterious sect of worshippers of Shitala who ground viral
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Once we teach our innate immune cells to attack malignant cells in humans, we will have invented an entirely new mode of cell therapy that harnesses inflammation. Perhaps we might describe it, metaphorically, as a pox on cancer.
The shaft or stem of the Y has yet other purposes: once bound to a cell, it also attracts a cascade of toxic immune proteins from the blood to attack microbial cells. An antibody, in short, can be conceived as a molecule with multiple parts—the binding prongs that attach themselves to the antigen, and a shaft that enables it to liaise with the immune system to become a potent molecular killer. These two distinct functions of the antibody—antigen binder and immune activator, are combined in one molecule, with a form—an immunological pitchfork—that is consummately linked to its function.
There is an Indian legend of Yashodhara, mother of Krishna, one of the major Hindu deities, opening his infant mouth because he has swallowed a clod of dirt. She pries his teeth apart and witnesses the whole universe inside him: the stars, the planets, the million suns, the whirling galaxies, the black holes. Was each of our B cells carrying a reflected cosmos—the cognate reverse of every antigen in the universe?
A wondrous process occurs when a B lymphocyte, displaying the right receptor, meets a foreign antigen. As Lewis Thomas wrote in his book The Lives of a Cell: Notes of a Biology Watcher (1974): “When the connection is made, and a particular lymphocyte with a particular receptor is brought into the presence of the particular antigen, one of the greatest small spectacles in nature occurs. The cell enlarges, begins making new DNA at a great rate and turns into what is termed, appropriately, a blast. It then begins dividing, replicating itself into a new colony of identical cells all labeled with
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As Ehrlich had imagined back in 1891, these blasts now begin to secrete the receptor into the blood. Freed from the B cell’s membrane and now floating in the blood, the receptor “becomes” the antibody.I And when the antibody is bound to its target, it can summon a cascade of proteins to poison the microbe and can recruit macrophages to devour, or phagocytose, it. Decades later, researchers demonstrated that some of these activated B cells don’t simply peter out. They persist in the body in the form of memory cells. In Thomas’s words, “The new cluster [of cells stimulated by the antigen] is a
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When an antigen binds to it, the B cell gets activated. It switches from displaying the receptor on its surface to secreting it, in the form of an antibody, into the blood. Even further mutations accumulate in the B cell, refining the antibody’s binding to the antigen.II Ultimately, the B cell matures into a cell so single-mindedly dedicated to antibody production that its structure and metabolism are altered to facilitate the process. It is now a cell dedicated to making antibodies—a plasma cell. Some of these plasma cells also become long lived and retain the memory of the infection.
A macrophage or monocyte might present digested bits of a microbe or summon B cells to the site of an infection, but it’s the antibody-secreting B cell that binds some part of the microbe. The cell that carries a receptor which binds the microbe is activated to clonally expand and begins to secrete the antibody into the blood. Finally, that B cell changes its internal landscape and becomes part of the memory B cell compartment, thereby retaining the memory of the original inoculum.
“To understand T cell virology, learn to think like a virus,” Enzo told me. And so I did. I would “become” EBV one afternoon, and herpes the next. (The latter involved having some sense of humor.)
so bad that it was not even wrong.
killer T cells: T lymphocytes that recognize virus-infected cells and souse them with toxins until they shrivel and die, thereby purging the microbe taking refuge there. These cytotoxic (cell-killing) T cells, brandished a particular marker on their surfaces: CD8, a type of protein. The peculiar thing about these CD8-positive T cells, Zinkernagel and Doherty discovered, was that they had a capacity to recognize viral infections only in the context of the self. Consider that thought: your T cells can recognize virally infected cells only if they come from your body, not someone else’s.III A
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It is as if the MHC protein is a frame. Without the right frame, or context (“yourself”), the T cell cannot even see the picture, even if it is a distorted version of the “self.” And without the picture in the frame (presumably, some part of the virus—an infected self), again, the T cell cannot recognize the infected cell. It needs both the pathogen and the self—the picture and the frame.V
It is one of the cleverest ways of repurposing a cell’s intrinsic molecular apparatus: it takes the natural waste-disposal factory of the body, treats the viral protein as if it were any other protein meant for disposal, mounts it on a protein carrier, and pushes it out of a hatch and onto the cell’s surface. The inside is now outside. The cell has sent a sampling of its inner life, bound in the correct frame, to be surveyed by the immune system. When a CD8 cell comes by, sniffing the cell surface, it will find a large selection of peptides from the interior of a cell loaded on its
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Once phagocytosed, targeted to the lysosome and degraded, bacteria and viruses are chopped into peptides.VII And just as the class I MHC molecule frames and presents a cell’s internal peptides to T cells, a related class of proteins—called class II MHCs—presents mostly external peptides to T cells. Its structure, too, is similar: a hand holding up two halves of a bun, with a groove for the peptide in the middle.
The internal peptides, presented by class I MHCs, as Zinkernagel and Doherty had found, are detected by a set of T cells called CD8 killer T cells. The CD8 cells, you’ll remember, kill the infected cell, purging the virus in the process. In contrast, a majority of peptides derived from pathogens outside the cell (and a few from the cell’s interior that end up in the lysosome) are presented by class II MHCs. These are detected by a second class of T cells, called CD4 T cells. The CD4 T cell isn’t a killer (again, there’s a logic to this. The virus is already dead and minced to pieces; why kill
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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.)
The identity of the AIDS-causing virus was finally revealed on March 20, 1983, when the French researcher Luc Montagnier, working with Françoise Barré-Sinoussi, published a paper in Science magazine describing the isolation of a novel virus from the lymph nodes of several patients with AIDS. Over the next year, as the disease swept through Europe and America, killing thousands, virologists debated whether this virus was, indeed, the cause of AIDS. In 1984, biomedical researcher Robert Gallo’s lab at the National Cancer Institute settled the debate for good: the team published four papers in
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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. Its functions are diverse. Its work begins, as we read before, when it detects peptides from pathogens, loaded on class II MHC molecules, and presented by cells. Then it jump-starts the immune response, activating it, sending alarms, enabling B cell maturation, and
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What factors had contributed to the potential cure? The particular strain of HIV? The low viral load before the transplants? The “engineering” of Brown’s immune system after the transplant? Answers to these questions will guide the next wave of HIV therapies. We will learn about where the virus hides, how to attack its reservoirs, how cells might resist infection. Most importantly, we’ll learn about how the immune system can be taught to recognize this most devious of pathogens.
The article is called “Ralph M. Steinman: A Man, a Microscope, a Cell, and So Much More.” It is the story of virtually every researcher who inhabits this book captured in three words: A scientist. A scope. A cell.
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. They termed the self atman. (There are many other Sanskrit words for the self besides atman, but it is the one that holds the most meaning.) The universal, multitudinous self, in contrast, was the Brahman. For these philosophers, the self was an ideal fusion of atman and Brahman, or
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self versus nonself. By the late 1930s, building on Gorer’s work, he slowly narrowed in on a set of genes that determined tolerance. He termed them H genes, for histocompatibility genes—histo from tissue, and compatibility because of their capacity to render foreign tissue to be accepted as self. It was some version of these H genes, Snell realized, that defines the boundary of the immunological self. If organisms shared the H genes, you could transplant tissue from one organism to another. If they didn’t, the transplant would be rejected.
Perhaps the most profound advance in the field occurred when the identity of these H genes was finally revealed. Most of them turned out to encode functional MHC molecules—the very molecules, recall, that had been implicated in how a T cell recognizes its target.
In immunology, as with any science, there are moments of grand synthesis, when seemingly disparate observations and seemingly inexplicable phenomenon converge on a single mechanistic answer. How does the self know itself? Because every cell in your body expresses a set of histocompatibility (H2) proteins that are different from the proteins expressed by a stranger’s cells. When a stranger’s skin, or bone marrow, is implanted into your body, your T cells recognize these MHC proteins as foreign—nonself—and reject the invading cells.
Humans have multiple “classical” major histocompatibility genes, and potentially many others, of which at least three, and possibly more, are strongly related to graft compatibility versus rejection. One gene, called HLA-A, has more than a thousand variants, some common and some very rare. You inherit one such variant from your mother and one from your father. A second such gene, HLA-B, also has thousands of variants. You might have guessed already that the number of permutations between just two such highly variable genes is mind-boggling. The chances that you’d share such a barcode with a
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In short, H2 (or HLA) molecules serve two linked purposes. They present peptides to a T cell so that a T cell can detect infections and other invaders and mount an immune response. And they are also the determinants by which one person’s cells are distinguished from another person’s cells, thereby defining the boundaries of an organism. Graft rejection (likely important for primitive organisms) and invader recognition (important for complex, multicellular organisms) are thus combined into a single system. Both functions repose in the T cell’s capacity to recognize the MHC peptide complex, or
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“Recognition that an antigenic determinant is foreign requires that it shall not have been present in the body during embryonic life”
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
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But T cell deletion in the thymus—a mechanism called central tolerance because it affects all T cells during their central maturation—isn’t enough to guarantee that immune cells don’t end up attacking the self. Beyond central tolerance, there is a phenomenon called peripheral tolerance; here tolerance is induced once the T cells have left the thymus.
One of these mechanisms involves a strange and mysterious cell called the T regulatory cell (T reg). It looks almost identical to a T cell, except that rather than incite an immune response, the T reg suppresses it. T regulatory cells zero in on sites of inflammation and secrete soluble factors—anti-inflammatory messengers—that dampen the activity of 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. Sometime in the future, we will understand why
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Most human cancers, though, represent a vastly more subtle challenge for 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. Cancer, in short, may be a rogue self—but it is, indubitably, a self. And second: the cancer cells that ultimately form a clinically relevant illness in a human arise through an
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Intrigued by this activation of T cells against a tumor, Allison and several other researchers spent more than a decade trying to deepen their understanding of the protein’s function. As all the earlier experiments had shown, they found that CTLA4 was a system to prevent horror autotoxicus; it was a T cell’s trigger lock. Under normal circumstances, when CTLA4 on activated T cells meets its cognate binder, called B7,III that is present on the surface of cells of the lymph nodes, where T cells mature, the safety switch is turned on. The maturing T cells are disabled from attacking the self but
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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!”
Blood. A cosmos of cells. The restless ones: red blood cells. The guardians: multilobed neutrophils that mount the first phases of the immune response. The healers: tiny platelets—once-dismissed as fragmentary nonsense—that redefined how we respond to breaches in the body. The defenders, the discerners: B cells that make antibody missiles; T cells, door-to-door wanderers that can detect even the whiff of an invader, including, possibly, cancer.
And blood? It is a conglomerate of organs, a system of systems. It has built training camps for its armies (lymph nodes), highways and alleys to move its cells (blood vessels). It has citadels and walls that are constantly being surveyed and repaired by its residents (neutrophils and platelets). It has invented a system of identification cards to recognize its citizens and eject intruders (T cells) and an army to guard itself from invaders (B cells). It has evolved language, organization, memory, architecture, subcultures, and self-recognition. A new metaphor comes to mind. Perhaps we might
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Why, how—why, why, why, how, how—can a cancer cell circumvent T cells designed to recognize and kill it? This question haunts immunotherapy today. Something about a solid tumor—perhaps the environment that it has created around itself—can circumvent and inhibit even the most potent reactivation of T cells. What is that “something”? The most solid evidence, and this is not a play on words, is that the immune attack on a cancer can occur only if a fully active lymphoid organ, containing neutrophils, macrophages, helper T cells, killer T cells, and an organized cellular structure, can be formed
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—Giovanni Boccaccio, The Decameron
I think, sometimes, of a legend. Bali, a demon king, has conquered three worlds—the earth, the underworld, and the heavens. A tiny man with smoky eyes and an umbrella, Vamana—Vishnu’s avatar—appears before him and asks him to grant him a single wish. His arrogance inflated into munificence, Bali, the demon king, agrees. Vamana asks for something ludicrously small: a square plot of land whose edges are defined by the distance that he might cover in three strides. The man is—what—two arm lengths tall? He wants a few square feet of a kingdom that stretches to infinity? Bali laughs it off; yes, of
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Why, you might ask, do the medical mysteries of the Covid-19 pandemic sit at the center of a book on cell biology? Because cell biology sits at the center of the medical mysteries. Everything we understood about cells and their interactions with each other—how the innate immune system responds to a pathogen; how immune cells communicate with each other; how a virus, growing so tenaciously inside a lung cell, can cause a presymptomatic infection without alerting other cells around it; how the cells of the gastrointestinal system may act as first responders to a pathogen—has to be rethought and
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In 2020, a group of Dutch researchers, looking for genes that might increase susceptibility to severe Covid, found the glimpse of an answer. The group identified two sibling pairs from different families, four young men, who had suffered unusually aggressive forms of the disease. Genetic sequencing revealed that one pair had inherited an inactivating mutation in a gene, TLR7 (fraternal siblings, on average, will have half their genes in common). Astonishingly, the second pair of brothers had also inherited a mutation in that very gene that appeared to decrease its activity (the exact mutation
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The cellular “hijack” involves an uncannily devious trick: even as it converts the cell into a factory to produce millions of virions, SARS-COV2 stops the infected cell from secreting type 1 interferon. At Rockefeller University in New York, Jean-Laurent Casanova converged on the same conclusion: 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
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“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.”
Imagine another character now, except surrounded by half-ghosts. Some of these “characters”—like type I interferon, the toll-like receptor, or the neutrophil—are mostly visible, except they exist in the half-light of visibility. We think we know and understand them, but we don’t, really. Some only cast shadows. Some are completely invisible. Some mislead us about their identities. And there are others around us whose presence we cannot even sense. We haven’t even met them, or named them, yet. I, too, have a name for this condition: scientist. We look, we create, we imagine—but find only
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But triumphalism fails in the face of more than six million deaths. 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.