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October 26, 2022 - February 5, 2023
It’s all a circle, so let’s begin with the right side. The right-sided pump collects blood from the veins of the body. Exhausted and depleted, having delivered oxygen and nutrients to the organs, “venous” blood (often darker red than bright crimson) pours into the upper right chamber called the right atrium. It then passes through a valve and is moved into the pumping chamber, the right ventricle. A powerful heave from the right ventricle pumps the blood to the lungs. This is the right-sided circuit—veins to heart to lung. The lungs, having received blood from the right side of the heart,
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one peculiarity of the system is that it is the release of actin from myosin—not the binding of the fibers—that requires energy. When an organism dies, and the source of energy is lost, the muscle fibers, unable to unclasp their fists, are caught in a permanent grip—bound. The cellular ropes in every muscle tighten. The body hardens and contracts into the permanent clasp of death—the phenomenon that we call rigor mortis).
What is that “stimulus”? It’s the movement of ions—principally calcium—in and out of cells through specialized channels on the membranes of heart cells. In its resting state, the heart cell has low levels of calcium. When it is stimulated to contract, calcium floods into a heart cell, and it instigates contraction. And calcium’s entry is a self-feeding loop: the entry of calcium releases more calcium from the heart cell, resulting in a sharp, steep spike in calcium levels. The interconnections between the cells—those “junctions” that were identified in the 1950s—carry the ionic message from
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There are two final cellular elements of the heart that are essential to its function. First, there are valves between the chambers to ensure that blood does not flow backward. The cells of the atria—the collecting chambers—contract first sending blood into the ventricles. The valves between the atria and ventricles close, making a flapping noise: Lub, the first heart sound. And after that, the cells of the ventricle contract in a similarly coordinated manner. The outlet valves of the ventricles close: Dub, the second heart sound. Lub-Dub, Lub-Dub. The sound of a citizenry in lockstep, working
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And unlike Golgi, what Cajal saw was a radically different organization of cells. There was no tangled “reticulation” in the nervous system, no hodgepodge of wiry extensions. Rather, there were individual neuronal cells, with intricate, delicate anatomy, that reached out to connect with individual neuronal cells. He sketched them by hand, in black ink, producing among the most beautiful drawings in the history of science. Some neurons were like thousand-branched trees, with dense arbors of extensions above, a pyramidal cell body in the middle, and a stem-like extension below. Some were like
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For centuries, scientists had believed that nerves were hollow conduits, like pipes, and some fluid, or air—pneuma—flowing through them carried a wave of information from one nerve to the next, and from the nerve to a muscle, ultimately causing that muscle to contract. According to the “balloonist” theory, as it was called, the muscle was a balloon, and when it was filled with pneuma, it swelled like an air-filled bladder.
Imagine, now, that the army of invading ions, a charge (indeed, literally so) marches past the dendrites toward the neuron’s cell body—the soma—and reaches a pivotal point in the neuron, called the “axon hillock.” It is here that the critical biological cycle that enables nerve conduction is set into motion. If the pulse that reaches the axon hillock is greater than a set threshold, the ions begin a self-fulfilling loop. The ions stimulate the opening of more channels in the axon. In biology, when a chemical stimulates the release of the very same chemical, it sparks a positive feedback
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The boutons that mark the end of one nerve almost touch the dendrites of the next nerve. But they don’t quite touch. “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. It is tiny; you could wave it away. Perhaps it’s an artifact of microscopy or staining. 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
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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. There’s sand in the air everywhere you look, and a completely new pathway of thinking is needed. Quantum theory serves as a good example. In the early 1900s, as the atomic and subatomic worlds were discovered, the heuristic principles of Newtonian physics just would not suffice, and a shifted paradigm about this atomic/subatomic world was required to get out of the
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Neural connections between the eyes and the brain are formed long before birth, establishing the wiring and the circuitry that allow a child to begin visualizing the world the minute she emerges from the womb. Long before the eyelids open, during the early development of the visual system, waves of spontaneous activity ripple from the retina to the brain, like dancers practicing their moves before a performance. These waves configure the wiring of the brain—rehearsing its future circuits, strengthening and loosening the connections between neurons. (The neurobiologist Carla Shatz, who
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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.
Perhaps the singularly striking feature of synaptic pruning is that it uses an immunological mechanism to eliminate connections between neurons. Macrophages in the immune system phagocytose—eat—pathogens and cellular debris. Microglia in the brain use some similar proteins and processes to mark synapses that are to be nibbled—except, rather than ingesting pathogens, they ingest the bits of a neuron involved in the synaptic connections. It’s yet another captivating instance of repurposing: the very proteins and pathways that are used to clear pathogens in the body have been rejiggered to
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In the 1960s and 1970s, Greengard’s experiments had led him to a novel way of thinking about neuronal communication. Neurobiologists studying the synapse had largely described the communication between neurons to be a rapid process. An electrical impulse arrives at the end of the neuron—i.e., at the axon terminal. It causes the release of chemical neurotransmitters into a specialized space—the synapse. The chemicals, in turn, open channels in the next neuron, and ions surge in, reinitiating the impulse. This is the “electrical” brain—a box of wires and circuits (with a chemical signal—a
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“That’s why you have to listen to the metaphors,” Mayberg told me. The difference between a smile and laughter. There was a picture in her office of a stream with a deep sinkhole in the middle, where water gushed in from all sides. “A patient sent me that picture to describe her depression.” Another void, a hole. Vertical, inescapable traps. When Mayberg turned the stimulator on, the woman said she saw herself lifted out of the sinkhole and sitting on a rock above the water. She could see her former self in the hole—but she was on a rock, sitting above the hole. “These pictures, these
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The signals move from one organ to the next, carried by blood. 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.
Insulin, we now know, is synthesized by a particular subset of islet cells in the pancreas—beta cells—and its secretion is stimulated by the presence of glucose in the blood. It then travels all over the body. Virtually every tissue responds to insulin: the presence of sugar means that the extraction of energy, and everything that flows from energy—the synthesis of proteins and fats, the storage of chemicals for future use, the firing of neurons, the growth of cells—can proceed. It is, perhaps, among the most important of the “long range” messages that acts as a central coordinator and
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Sometime in the future we might encounter a new kind of diabetic patient with no injections, batteries, or beeping monitors (instead, the batteries and monitors will be worn, like those getting deep brain stimulation for Parkinson’s disease or depression). After so many winding errors and misconceptions, one murder, one throttling, one Nobel Prize split into four—and that unforgettable moment of a blue stain spreading on a cluster of cells—we may have solved the conundrum of the two-minded organ and made it into a bioartificial self. Once that neo-organ integrates into our bodies, the
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Deep within the kidney lies a multicellular anatomical structure called the nephron. Each nephron—first identified by cellular anatomists in the late 1600s—can be imagined as a mini-kidney. The nephron is the site where the blood and kidney cells meet, and the first drops of urine are generated. The circulation of blood carries the excess salt, dissolved in plasma, to the kidneys. The blood vessels split and split further to form finer and finer-walled arteries. Finally, the thinnest arteries whirl around themselves to form a thin-walled nest of cells—so delicate and porous that the liquid,
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Back, then, to the sodium that you consumed. The excess sodium causes a hormonal system, regulated by the kidney and the adrenal gland, which sits just above the kidney, to decrease its signal. The cells in the tubule respond to these changes by excreting the excess sodium into urine, thereby discarding the salt and returning the sodium level to normal. The salt is also detected by specialized cells in the brain that monitor the overall concentration of salts in the blood, a property called osmolality. These cells, sensing a high osmolality, send out another hormone to cause the cells in the
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And the alcohol? The last cell type in this trio of orchestrating cells (or quarto, if you count the brain) are the cells of the liver—hepatocytes. The liver cell is functionally specialized for both storage and waste disposal, secretion, protein synthesis, among dozens of many other functions. But waste disposal is so essential for the body—and the liver so deeply specialized for it—that it’s worth its own focus.
Alcohol, for instance, is detoxified in a series of reactions, until it is broken down into a harmless chemical. There are even specialized cells within the liver that eat dead or dying cells—red cells, for instance. Reusable products from the dead cells are recycled. Others are dispensed into the intestines or excreted by the kidney. Liver cells, in short, are also part of the “orchestra” of regulation and constancy—except, unlike pancreatic islet cells, they perform their regulation locally. The pancreatic cell maintains metabolic constancy, the kidneys salt constancy. The liver maintains
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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.
Stem cells don’t simply transform themselves into other cells (a process called differentiation) to build what the body needs and then, their work done, quietly disappear. They are more than the progenitors of other cells. They also replicate themselves—in an unrefined, undifferentiated state—so that they can stick around to answer the call later when the blood system needs rebuilding. —Joe Sornberger, Dreams and Due Diligence
But to be a true stem cell, this must be the oddest of great-great-great-grandfathers. It must also give birth to a copy of itself that can maintain the replenishment of the lineage. This great-great-great-grandfather, besides birthing a child (that will go on to establish an enormous lineage), must also birth a copy of itself—an eternally alive twin. And once this self-renewing great-great-great-grandfather is born, the process of regeneration can become limitless. There’s a mythic quality to such a setup—and indeed, in myths, one often finds attempts by powerful kings or Gods to make backup
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Mathé deduced that this wasting disease was caused by immune response in the donor marrow attacking the body of the transplanted patients. The guest was attacking the host. This response is the consequence of an ancient system for maintaining the sovereignty of organisms (and rejecting invading cells)—except in bone marrow transplants, the direction of sovereignty is reversed. Like a mutinous crew forced onto an unfamiliar ship, the donor’s immune cells recognize the body around them as foreign and attack it. The other (that is, previously the graft) becomes the self, and the self, ipso facto,
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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.
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
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Since Yamanaka’s discovery, for which he won the Nobel Prize in 2012, 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
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Superficially, bone might look like a chunk of hardened calcium, but it is, in fact, made of a multiplicity of cells. The most familiar are cartilage cells—technically called chondrocytes—and there are two unfamiliar-sounding cell types. The second is the “osteoblast”—the cell that deposits calcium and other proteins to form a calcified matrix in layers, and then get trapped in its own deposit to form new bone. It is the bone-making, bone-depositing cell: typically, the osteoblasts thicken and lengthen the bone (my mnemonic for its name is the letter “b,” for “bone making”). The third is an
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Bone is not just an organ with a single supply of rejuvenating cells; it is a chimera of rejuvenation. It has at least two sources for two sites. There are growth-plate resident OCR (or OCHRE) cells, which form lengthening bone. They arise early in development and then gradually decay with age. And there are LR cells that arise later in adolescence and adulthood that participate in the maintenance of thickness of long bones, and bone fracture repair.
Toghrul, Jia, Dan, and I sent our data for publication in the winter of 2021. We proposed a radically new hypothesis about osteoarthritis. It isn’t merely a degeneration of cartilage cells, caused by grind and tear. It is, first, an imbalance caused by the death of Gremlin-marked cartilage progenitor cells that cannot generate adequate bone and cartilage to keep up with the demands of the joint. And so we have a theory to answer the fourth age-old mystery: Why doesn’t cartilage in joints get repaired, just as a bone fracture does, in adults? Because the repairing cells die during the injury.
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In cell biological terms, then, it might be easier to imagine injury, or aging, for that matter, more abstractly, as a furious battle between a rate of decay and a rate of repair, with each rate unique for every individual cell, and individual organ. 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
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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
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Those who have not trained in chemistry or medicine may not realize how difficult the problem of cancer really is. It is almost—not quite, but almost—as hard as finding some agent that will dissolve away the left ear, say, and leave the right ear unharmed. —William Woglom,
“We biomedical scientists are addicted to data, like alcoholics are addicted to cheap booze,” Michael Yaffe, a cancer biologist from MIT, wrote in the journal Science Signaling. “As in the old joke about the drunk looking under the lamppost for his lost wallet, biomedical scientists tend to look under the sequencing lamppost where the ‘light is brightest’ [because that’s where it’s easiest to see]—that is, where the most data can be obtained as quickly as possible. Like data junkies, we continue to look to genome sequencing when the really clinically useful information may lie someplace else.”
do not know which to prefer, The beauty of inflections Or the beauty of innuendoes, The blackbird whistling Or just after. —Wallace Stevens, “Thirteen Ways of Looking at a Blackbird”
Many readers might read the word song as metaphorical. But in my reading, it’s far from a metaphor. 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
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To build new humans out of cells, we need knowledge that is not just names, but the interconnectedness between names. Not addresses, but neighborhoods; not identification cards, but personalities, stories, and the histories that accompany them.
Decades ahead of her time, the geneticist Barbara McClintock called the genome a “sensitive organ of the cell.” The words organ and sensitive reflected ideas totally foreign to geneticists in the fifties and sixties. Arguing against the atomistic gene-by-gene approach favored by geneticists, McClintock proposed, the genome could only be interpreted as a whole—as a “sensitive organ”—that was responsive to its environment.
By that same logic, cells, by themselves, are incomplete explanations for organismal complexities. We need to factor in cell-cell interactions, and cell-environment interactions—ushering in holism in cell biology. We possess rudimentary terms for these interactions—ecologies, sociologies, “interactomes”—but still lack models, equations, and mechanisms to understand them. I return, often, to think of disease as a violation of the social compacts between cells.
Part of the problem is that the word holism has become scientifically defiled. It has become synonymous with the mushing of everything we understand into a malfunctioning, soft-bladed (and soft-headed) blender. T...
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Universal principles satisfy us—one equation good—because they satisfy our belief in an ordered universe. But why must “order” be so soldierly, so singular, so unifest (as opposed to manifest)? Perhaps one manifesto for the future of cell biology is to integrate “atomism” and “holism.” Multicellularity evolved, again and again, because cells, while retaining their boundaries, found multiple benefits in citizenship. Perhaps we, too, should begin to move from the one to the many. That, more than any other, is the advantage of understanding cellular systems, and, beyond that, cellular ecosystems.
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All cells come from cells. The first human cell gives rise to all human tissues. Ipso facto, every cell in the human body can be produced, in principle, from an embryonic cell (or stem cell). Although cells vary widely in their form and function, there are deep physiological similarities that run through them. These physiological similarities can be repurposed by cells for specialized functions. An immune cell uses its molecular apparatus for ingestion to eat microbes; a glial cell uses similar pathways to prune synapses in the brain. Systems of cells with specialized functions, communicating
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But I too made things That may one day be Better versions of me. —Walter Shrank, “Battle Cries of Every Size,” 2021
“Accepting and cherishing the raw material you’ve been given to work with.” What raw material? Sandel’s and Saletan’s discussion focuses on genes—and indeed, gene therapy, gene editing, and genetic selection has preoccupied ethicists, doctors, and philosophers for the last decade. But genes are lifeless without cells. The real “raw material” of the human body is not information, but the way that information is enlivened, decoded, transformed, and integrated—i.e., by cells. “The genomic revolution has induced a kind of moral vertigo,” Sandel writes. But it is the cellular revolution that will
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Nestled at the center of each of the proteins is another chemical: heme. And at the center of heme sits an atom of iron. It is a doll-within-a-doll-within-a-doll scheme. Red blood cells contain hemoglobin molecules that contain heme that, in turn, clasps iron atoms. It’s the iron that binds and unbinds the oxygen.