# The Song of the Cell  ## Metadata - Author: [[Siddhartha Mukherjee]] - Full Title: The Song of the Cell - Category: #books ## Highlights - perhaps more surprisingly, there was a deep uniformity in the construction of the tissues. Each part of the plant was built, bricolage-like, out of autonomous, independent units—cells. “Each cell leads a double life,” Schleiden would write a year later, “an entirely independent one, belonging to its own development alone; and an incidental one, in so far as it has become part of a plant.” A life within a life. An independent living being—a unit—that forms a part of the whole. A living building block contained within the larger living being. ([Location 45](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=45)) - Tags: [[blue]] - Animals and plants—as seemingly different as living organisms could be. Yet, as both Schwann and Schleiden had noticed, the similarity of their tissues under the microscope was uncanny. Schwann’s hunch had been right. That evening in Berlin, he would later recall, the two friends had converged on a universal and essential scientific truth: both animals and plants had a “common means of formation through cells.” ([Location 55](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=55)) - Tags: [[blue]] - But cancer cells don’t “invent” any of these properties. They don’t build anew, they hijack—or, more accurately, the cells that are fittest for survival, growth, and metasisis are naturally selected. The genes and proteins that cells use to generate the building blocks required for growth are appropriated from the genes and proteins that a developing embryo uses to fuel its fierce burst of expansion during the first days of life. The pathways used by the cancer cell to move across vast bodily spaces are commandeered from those that allow inherently mobile cells in the body to move. The genes that enable unfettered cell division are distorted, mutated versions of genes that allow cell division in normal cells. Cancer, in short, is cell biology visualized in a pathological mirror. ([Location 122](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=122)) - Tags: [[blue]] - Emily’s trial involved infusing her body with her own T cells. But these T cells had to be weaponized, via gene therapy, to recognize and kill her cancer. Unlike Sam, who had received drugs to activate immunity inside his body, Emily’s T cells had been extracted and grown outside her body. This form of treatment had been pioneered by the immunologist Michel Sadelain at the Sloan Kettering Institute in New York and by Carl June at the University of Pennsylvania, building on earlier work by the Israeli researcher Zelig Eshhar. ([Location 179](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=179)) - Tags: [[blue]] - radical concept swept through biology and medicine, touching virtually every aspect of the two sciences, and altering both forever. Complex living organisms were assemblages of tiny, self-contained, self-regulating units—living compartments, if you will, or “living atoms,” as the Dutch microscopist Antonie van Leeuwenhoek called them in 1676. Humans were ecosystems of these living units. We were pixelated assemblages, composites, our existence the result of a cooperative agglomeration. We were a sum of parts. ([Location 247](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=247)) - Tags: [[blue]] - The transformation of medicine made possible by our new understanding of cell biology can be broadly divided into four categories. The first is the use of drugs, chemical substances, or physical stimulation to alter the properties of cells—their interactions with one another, their intercommunication, and their behavior. Antibiotics against germs, chemotherapy and immunotherapy for cancer, and the stimulation of neurons with electrodes to modulate nerve cell circuits in the brain fall in this first category. The second is the transfer of cells from body to body (including back into our own bodies), exemplified by blood transfusions, bone marrow transplantation, and in vitro fertilization (IVF). The third is the use of cells to synthesize a substance—insulin or antibodies—that produces a therapeutic effect on an illness. And most recently, there is a fourth category: the genetic modification of cells, followed by transplantation, to create cells, organs, and bodies endowed with new properties. ([Location 254](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=254)) - Tags: [[blue]] - In 1922, a fourteen-year-old boy with type 1 diabetes was resuscitated from a coma—born anew, as it were—by the infusion of insulin extracted from the pancreatic cells of a dog. In 2010, when Emily Whitehead received her infusion of CAR (chimeric antigen receptor) T cells, or twelve years later, when the first patients with sickle cell anemia are surviving, disease-free, with gene-modified blood stem cells, we are transitioning from the century of the gene to a contiguous, overlapping century of the cell. ([Location 267](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=267)) - Tags: [[blue]] - Life’s definition, as it stands now, is akin to a menu. It is not one thing but a series of things, a set of behaviors, a series of processes, not a single property. To be living, an organism must have the capacity to reproduce, to grow, to metabolize, to adapt to stimuli, and to maintain its internal milieu. Complex, multicellular living beings also possess what I might call “emergent” properties: properties that emerge from systems of cells, such as mechanisms to defend themselves against injury and invasion, organs with specialized functions, physiologic systems of communication between organs and even sentience and cognition. And it is not a coincidence that all these properties repose, ultimately, in the cells, or systems of cells. In a sense, then, one might define life as having cells, and cells as having life. ([Location 278](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=278)) - Tags: [[blue]] - What is a cell, anyway? In a narrow sense, a cell is an autonomous living unit that acts as a decoding machine for a gene. Genes provide instructions—code, if you will—to build proteins, the molecules that perform virtually all the work in a cell. Proteins enable biological reactions, coordinate signals within the cell, form its structural elements, and turn genes on and off to regulate a cell’s identity, metabolism, growth, and death. They are the central functionaries in biology, the molecular machines that enable life.I ([Location 289](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=289)) - Tags: [[blue]] - By decoding, I mean that molecules within a cell read certain sections of the genetic code, like musicians in an orchestra reading their parts of a musical score—the cell’s individual song—thereby enabling a gene’s instructions to become physically manifest in the actual protein. Or, put more simply, a gene carries the code; a cell deciphers that code. A cell thus transforms information into form; genetic code into proteins. A gene without a cell is lifeless—an instruction manual stored inside an inert molecule, a musical score without a musician, a lonely library with no one to read the books within it. A cell brings materiality and physicality to a set of genes. A cell enlivens genes. ([Location 297](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=297)) - Tags: [[blue]] - a cell is not merely a gene-decoding machine. Having unpacked the code by synthesizing a select set of proteins that is encoded in its genes, a cell becomes an integrating machine. A cell uses this set of proteins (and the biochemical products made by proteins) in conjunction with one another to start coordinating its function, its behavior (movement, metabolism, signaling, delivering nutrients to other cells, surveying for foreign objects), to achieve the properties of life. And that behavior, in turn, manifests as the behavior of the organism. ([Location 303](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=303)) - Tags: [[blue]] - And finally, a cell is a dividing machine. Molecules within the cell—proteins, again—initiate the process of duplicating the genome. The internal organization of the cell changes. Chromosomes, where the genetic material of a cell is physically located, divide. Cell division is what drives growth, repair, regeneration, and, ultimately, reproduction, among the fundamental, defining features of life. ([Location 309](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=309)) - Tags: [[blue]] - The Yale University virologist Akiko Iwasaki told me that the central pathology caused by SARS-CoV2 (severe acute respiratory syndrome coronavirus 2) was “immunological misfiring”—a dysregulation of immune cells. I had not even heard the term before, but its immensity hit me: at its core, the pandemic, too, was a disease of cells. Yes, there was the virus, but viruses are inert, lifeless, without cells. Our cells had awoken the plague and brought it to life. To understand crucial features of the pandemic, we would need to understand not just the idiosyncrasies of the virus but also the biology of immune cells and their discontents. ([Location 342](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=342)) - Tags: [[blue]] - But if you looked down a microscope at your skin and mine, or your liver and mine, you would find them strikingly alike. And you’d realize that all of us were, in fact, built out of living units: cells. The first cell gave rise to more cells, and then divided to form even more, until our livers and guts and brains—all the elaborate anatomical architectures in the body—were gradually formed. When did we realize that humans were, in fact, composites of independent, living units? Or that these units are the basis of all the functions that the body is capable of—in other words, that our physiology reposes, ultimately, in cellular physiology? And conversely, when did we posit that our medical fates and futures were intimately linked to the changes in these living units? That our diseases are consequences of cellular pathology? ([Location 385](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=385)) - Tags: [[blue]] - Was there some deeper organizing principle that connected these organs, and their diffuse and mystifying disorders? Could one even think of human pathology in a systematic manner? Perhaps the answer was not to be found in visible anatomy but rather in microscopic anatomy. Indeed, by analogy, eighteenth-century chemists had already begun to discover that the properties of matter—the combustibility of hydrogen or the fluidity of water—arose from the emergent properties of invisible particles, molecules, and atoms that comprised them. Was biology perhaps similarly organized? ([Location 465](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=465)) - Tags: [[blue]] - Hooke’s intelligence was phosphorescent and elastic, like a rubber band that glows as it stretches. He would enter disciplines and then expand and illuminate them as if by an internal light. He wrote extensively about mechanics, optics, and material sciences. In the aftermath of the Great Fire of London, which raged for five days in September 1666, destroying four-fifths of the city, Hooke helped the esteemed architect Christopher Wren survey and reconstruct buildings. He built a powerful new telescope through which he could visualize the surface of Mars, and he studied and classified fossils. ([Location 581](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=581)) - Tags: [[blue]] - Hooke’s interest in microscopy eventually dwindled. His peripatetic intellect needed to roam widely, and he returned to optics, mechanics, and physics. Indeed, Hooke’s interest in virtually everything may have been his critical failing. The Royal Society’s motto, Nullius in verba, translated loosely as “Take no one’s word for evidence,” was his personal mantra. He loped from one scientific discipline to the next, offering potent insights, believing no one’s word, claiming dominion over critical parts of a science, but never asserting complete authority over any one subject. He had built himself on the model of the Aristotelian philosopher-scientist—an inquirer into all matters of the world, an adjudicator of all evidence—rather than the contemporary vision of the scientist as the authority on a single subject, and his reputation suffered as a result. ([Location 637](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=637)) - Tags: [[blue]] - Part of the explanation for this valley of silence has to do with the time required to develop instruments and model systems to answer these questions. Genetics had to await the work of the biologist Thomas Morgan, who explored the inheritance of traits in fruit flies in the 1920s to prove the physical existence of the gene, and, eventually, the birth of X-ray crystallography, the technique used to decipher the three-dimensional structure of molecules such as DNA, in the 1950s, to understand what genes look like in physical form. Atomic theory, first enunciated by John Dalton in the early 1800s, had to await the development of the cathode-ray tube in 1890, and the mathematical equations required to model quantum physics in the early twentieth century to elucidate the structure of the atom. Cell biology had to wait for centrifugation, biochemistry, and electron microscopy. ([Location 682](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=682)) - Tags: [[blue]] - You have to think of a cell in a different manner: not as an object under a lens but as a functional site for all physiological chemical reactions, as an organizing unit for all tissues, and as the unifying locus for physiology and pathology. You have to move from a continuous organization of the biological world to a description that involves discontinuous, discrete, autonomous elements that unify that world. ([Location 691](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=691)) - Tags: [[blue]] - What did cells do? “A cell is […] a kind of laboratory,” he posited. Pause for a moment to contemplate the scope of that thought. Using no more than basic assumptions about chemistry and cells, Raspail deduced that a cell performs chemical processes to make tissues and organs function. In other words, it enables physiology. He imagined the cell as the site for the reactions that sustain life. But biochemistry was in its infancy, and so the chemistry and reactions that occurred within this cellular “laboratory” were invisible to Raspail. He could describe it only as a theory. A hypothesis. ([Location 722](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=722)) - Tags: [[blue]] - The concept of the cell as a laboratory for an organism’s physiology returns to me: every cell growing in one of my incubators is a lab within a lab. The T cells that I had seen under the microscope in the Oxford lab were “Surveillance labs,” swimming in fluid to find viral pathogens hiding within other cells. The sperm cells that Leeuwenhoek had seen under his scope were “Information labs,” collecting hereditary information from a male, packaging it in DNA, and attaching a powerful swimming motor to deliver it to the egg cell for reproduction. The cell, as it were, is experimenting with physiology, passing molecules in and out, making chemicals and destroying chemicals. It is the laboratory of reactions that enables life. ([Location 733](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=733)) - Tags: [[blue]] - Schleiden and Schwann proposed the first two tenets of cell theory: All living organisms are composed of one or more cells. The cell is the basic unit of structure and organization in organisms. ([Location 802](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=802)) - Cells came from cells. And cellular physiology is the basis of normal physiology. If Virchow’s first tenet concerned normal physiology, his second was its converse; it reconceived medicine’s understanding of abnormality. What if dysfunctions in cells, he began to wonder, were responsible for malfunctions in the body? What if all pathology were cellular pathology? ([Location 877](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=877)) - Generations of anatomic pathologists had thought about diseases as the breakdown of tissues, organs, and organ systems. Virchow argued that they had missed the real source of the illness. Since cells were the unit blocks of life and physiology, Virchow reasoned, then the pathological changes observed in diseased tissues and organs should be traced back to pathological changes in the units of the affected tissue—in other words, to cells. To understand pathology, doctors needed to look for essential disruptions not just in visible organs but in the organ’s invisible units. ([Location 882](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=882)) - Virchow had refined Schwann and Schleiden’s cell theory by adding three more crucial tenets to the two founding ones (“All living organisms are composed of one or more cells,” and “The cell is the basic unit of structure and organization in organisms”): All cells come from other cells (Omnis cellula e cellula). Normal physiology is the function of cellular physiology. Disease, the disruption of physiology, is the result of the disrupted physiology of the cell. These five principles would form the pillars of cell biology and cellular medicine. They would revolutionize our understanding of the human body as assemblages of these units. They would complete the atomist conception of the human body, with the cell as its fundamental, “atomic” unit. ([Location 894](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=894)) - In a prescient lecture in 1845, Virchow defined life, physiology, and embryonic development as the consequences of cellular activity: “Life is, in general, cell activity. Beginning with the use of the microscope in the study of the organic world, far-reaching studies […] have shown that all plants and animals are, in the beginning […] a cell within which other cells develop to give rise again to new cells that together, undergo transformation to new forms, and, finally… constitute the amazing organism.” In a letter replying to a scientist who had asked him about the basis of illness, he identified the cell as the locus of pathology: “Every disease depends on an alteration of a larger or smaller number of cellular units in the living body, every pathological disturbance, every therapeutic effect, finds its ultimate explanation only when it’s possible to designate the specific living cellular elements involved.” These two paragraphs—the first proposing the cell as a unit of life and physiology, and the second proposing the cell as the unit locus of disease—are pinned on a board in my office. In thinking about cell biology, cellular therapies, and the building of new humans out of cells, I inevitably return to them. They are, as it were, the twin melodies that ring throughout this book. ([Location 922](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=922)) - “A social arrangement of parts.” “Every cell… derives its stimulus from another cell.” Imagine a cellular network—a social network—in which one node rents the whole net. Think of an actual fisherman’s net with a tear in a crucial site. You might find a random sagging point on the edge of that fishing net and conclude that it was the source of the problem. But you would miss the actual source—the epicenter—of the puzzle. You would focus on the periphery, while it was the center that would not hold. The next week, the pathologists brought his blood and bone marrow to the lab and began to dissect the subsets of cells, part by part, as if performing a surgical dissection—a “Virchovian analysis,” as I might describe it. “Ignore the B cells,” I urged them. “Let’s go through the blood, cell by cell, and look for the center of the sagging net.” ([Location 953](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=953)) - I also think of Rudolf Virchow, and the “new” pathology that he advanced. It isn’t sufficient to locate a disease in an organ; it’s necessary to understand which cells of the organ are responsible. An immune dysfunction might arise from a B cell problem, a T cell malfunction, or a glitch in any of the dozens of cell types that comprise the immune system. ([Location 972](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=972)) - Like hermits, microbes need only be concerned with feeding themselves; neither coordination nor cooperation with others is necessary, though some microbes occasionally join forces. In contrast, cells in a multicellular organism, from the four cells in some algae to the thirty-seven trillion in a human, give up their independence to stick together tenaciously; they take on specialized functions, and they curtail their own reproduction for the greater good, growing only as much as they need to fulfill their functions. When they rebel, cancer can break out. —Elizabeth Pennisi, Science, 2018 ([Location 1006](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=1006)) - Decomposition and disease might have seemed superficially very different, but Pasteur made a crucial link between them. He studied infections in silkworms, the decomposition of wine, and the transmission of anthrax in animals. In all these cases, he determined that infections were caused not by the consequence of floating particles of miasma, or divine malefactions, but by invasions by microbes—single-celled organisms that entered other organisms and caused pathological changes and tissue degeneration. ([Location 1034](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=1034)) - In 1884, eight years after he had concluded his anthrax experiments, Koch used his observations and experiments to postulate four tenets of a theory of causality for a microbial disease. To claim that a microbe causes a particular illness (in the way that, say, Streptococcus causes pneumonia or Bacillus anthracis causes anthrax), he proposed the following: (1) the organism/microbial cell must be found in a diseased individual, not in a healthy individual; (2) the microbial cell must be isolated and cultured from the diseased individual; (3) the inoculation of a healthy individual with the cultured microbe must recapitulate the essential features of the disease; and (4) the microbe must be re-isolated from the inoculated individual and match the original microorganism. ([Location 1060](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=1060)) - Snow had, in essence, partially united three disparate theories and fields of medicine. The first, epidemiology, tried to explain the patterns of human disease in aggregate. As a discipline, epidemiology “hovered” above people—hence epi (above) the demos (people). It attempted to understand human diseases in terms of their transmission across populations, their rise and fall in incidence and prevalence, and their presence or absence in particular geographic or physical distributions—the distance, say, from the Broad Street pump. Ultimately, it was a discipline designed to assess risk. But Snow had also edged a theory of epidemiology toward a theory of pathology, from inferred risk to a material substance. Some thing—a cell, no less—in that water was the cause of the infection. The geography, or the map of illness, was just a clue to its root cause; it was the sign of a physical substance moving through time and space, precipitating disease. Germ theory, the second field, still in its infancy, advanced the notion that infectious diseases were caused by microscopic organisms that invaded the body and disrupted its physiology. The third was the most audacious of all: cell theory, which held that the invisible microbe causing the disease was, in fact, an independent, living organism—a cell—that had contaminated the water. Snow had not seen the cholera bacillus under his microscope. But he had instinctively grasped that the causal elements had to be capable of reproducing in the body, reentering the sewage, and restarting an infectious cycle. The infectious units had to be living entities capable of copying themselves. ([Location 1128](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=1128)) - Each time I see a patient, I realize, I am probing the cause of his or her disease through three elemental questions. Is it an exogenous agent, such as a bacterium or virus? Is there an endogenous disturbance of cellular physiology? Is it the consequence of a particular risk, be it exposure to some pathogen, a family history, or an environmental toxin? ([Location 1142](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=1142)) - Every potent antibiotic—doxycycline, rifampin, levofloxacin—recognizes some molecular component of human cells that is different from a bacterial cell. In this sense, every antibiotic is a “cellular medicine”—a drug that relies on the distinctions between a microbial cell and a human cell. The more we learn about cell biology, the subtler distinctions we uncover, and the more potent antimicrobials we can learn to create. ([Location 1190](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=1190)) - But the transition from an RNA strand to a self-replicating RNA molecule is no small evolutionary feat. Most likely, two such molecules were needed—one to act as the template (i.e., the information carrier) and the other to make a copy of the template (i.e., a duplicator). When these two RNA molecules—template and duplicator—met each other, it was, perhaps, the most important and explosive evolutionary love affair in the history of our living planet. But the lovers had to avoid separation; if the two strands of RNA were to float away from each other, there would be no duplication and, by extension, no cellular life. And so some sort of structure—a spherical membrane—was likely needed to confine these components. These three components (a membrane, an RNA information carrier, and a duplicator) might have defined the first cell. If a self-replicating RNA system were bound by a spherical membrane, it would make more RNA copies within the confines of the sphere and grow in size by enlarging the membrane. At some point, biologists believe, the membrane-bound spheroid would split into two, each carrying the RNA duplicating system. (In lab experiments, Jack Szostak and his colleagues have shown that simple spheroidal structures, bound by membranes formed by fat molecules, can absorb more fat molecules, grow, and eventually split into two.) And from that point on, the protocell would launch its long evolutionary march toward the progenitor of the modern cell. Evolution would select more and more complex features of the cell, eventually replacing RNA with DNA as the information carrier. ([Location 1243](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=1243)) - there is one question that we will not and, perhaps, cannot answer. The origin of the modern cell is an evolutionary mystery. It seems to have left only the scarcest of fingerprints of its ancestry or lineage, with no trace of a second or third cousin, no close-enough peers that are still living, no intermediary forms. Lane calls it an “unexplained void… the black hole at the heart of biology.” ([Location 1270](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=1270)) - These, then, are among the first and most fundamental properties of the cell: autonomy, reproduction, and development. ([Location 1299](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=1299)) - Tags: [[blue]] - Cell biology finally makes possible a century-old dream: that of analysis of diseases at the cellular level, the first step toward their final control. —George Palade ([Location 1315](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=1315)) - Tags: [[blue]] - It is the membrane that defines the boundary; the outer limits of the self. Bodies are bound by a multicellular membrane: the skin. So is the psyche, by another membrane: the self. And so are houses and nations. To define an internal milieu is to define its edge—a place where the inside ends, and the outside begins. Without an edge, there is no self. To be a cell, to exist as cell, it must distinguish itself from its nonself. But what is the boundary of a cell? Where does one cell end and another begin? It also begins and ends with a membrane that surrounds it. ([Location 1319](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=1319)) - Tags: [[blue]] - Porosity, in short, represents an essential feature of life—but also an essential vulnerability of living. A perfectly sealed cell is a perfectly dead cell. But unsealing the membrane through portals exposes the cell to potential harm. The cell must embrace both: closed to the outside, yet open to the outside. ([Location 1328](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=1328)) - Tags: [[blue]] - Chemicals soluble in oil tended to enter the cell, he noted, while those insoluble in oil could not get in. The cell membrane must be an oily layer, Overton concluded, although he could not quite explain how a substance such as an ion or sugar, insoluble in fats, might enter or leave the cell. ([Location 1332](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=1332)) - Tags: [[blue]] - The final piece of the puzzle—how molecules such as sugar or ions pass in and out of the lipid bilayer, and how the cell communicates with its outside—was solved in 1972, nearly fifty years after Gorter and Grendel’s experiments. Two biochemists, Garth Nicolson and Seymour Singer, proposed a model in which proteins were embedded, like hatches, or channels, crossing the cell membrane. The lipid bilayer was not uniform or monotonous; it was porous by design. Proteins, floating in the membrane and spanning from inside to outside, allowed molecules to permeate the membrane and allowed other proteins and molecules to bind to the outside of the cell. ([Location 1342](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=1342)) - Tags: [[blue]] - the first thing you might note, once inside the cell, is that the cytoplasm has a molecular “skeleton” that maintains the form of the cell, just as a bony skeleton maintains an organism’s form.IV This scaffold, termed the cytoskeleton, is composed primarily of filaments of a ropy protein called actin, and tubular structures created by a protein called tubulin.V Unlike bones, though, these ropelike structures crisscrossing the cell are neither static nor merely structural. They form an internal system of organization. The cytoskeleton tethers components of the cell together, and is required for the movement of the cell. When a white blood cell creeps toward a microbe, it uses actin filaments, among other proteins, to push its feelers forward—gelling and un-gelling its front like the ectoplasmic movement of an alien. ([Location 1369](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=1369)) - Tags: [[blue]] - The ribosome captures RNAs and decodes their instructions to synthesize proteins. This cellular protein factory is itself made of proteins and RNA. It is yet another of life’s fascinating recursions, in which proteins make it possible to make other proteins. ([Location 1385](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=1385)) - Tags: [[blue]] - Building proteins is one of the cell’s major tasks. Proteins form enzymes that control the chemical reactions of life. They create structural components of the cell. They are the receptors for signals from the outside. They form pores and channels across the membrane, and the regulators that switch genes on and off in response to stimuli. Proteins are the workhorses of the cell. ([Location 1387](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=1387)) - Tags: [[blue]] - Mitochondria are found in all cells, but they are particularly densely packed in cells that need the most energy or that regulate energy storage, such as muscle cells, fat cells, and certain brain cells. They are wrapped around the tails of sperm, to provide them enough swimming energy to reach an egg. They divide within the cell, but when it’s the cell’s turn to reproduce, mitochondria are only split between the two daughter cells. In other words, they have no autonomous life; they can live only within cells. ([Location 1410](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=1410)) - Tags: [[blue]] - How does a cell generate energy? There are two pathways: one fast and one slow. The fast route occurs mainly in the protoplasm of the cell. Enzymes serially break down glucose into smaller and smaller molecules, and the reaction produces energy. Because the process doesn’t use oxygen, it is called anaerobic. In terms of energy, the end product of the fast pathway is two molecules of a chemical called adenosine triphosphate, or ATP. ATP is the central currency of energy in virtually all living cells. Any chemical or physical activity that requires energy—for instance, the contraction of a muscle or the synthesis of a protein—utilizes, or “burns,” ATP. The deeper slow burn of sugars to produce energy occurs in mitochondria. (Bacterial cells, lacking mitochondria, can use only the first chain of reactions.) Here the end products of glycolysis (literally, the chemical breakdown of sugar) are fed into a cycle of reactions that ultimately produce water and carbon dioxide. This cycle of reactions involves the use of oxygen (and is therefore called aerobic) and is a small miracle of energy production: it generates a much larger harvest of energy, again, in the form of ATP molecules. The combination of the fast and slow burn nets about the equivalent of thirty-two ATP molecules from every molecule of glucose. (The actual number is slightly lower, since not every reaction is perfectly efficient.) Over the course of a day, we generate billions of little canisters of fuel, to fire a billion little engines, in the billions of cells in our bodies. “Should all the billions of gently burning little fires cease to burn,” the physical chemist Eugene Rabinowitch wrote, “no heart could beat, no plant could grow upward defying gravity, no amoeba could swim, no sensation could speed along a nerve, no thought could flash in the human brain.” ([Location 1416](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=1416)) - Tags: [[blue]] - It was a ping-pong match in which both sides won. Microscopists would see subcellular structures; biochemists would assign functions to them. Or biochemists would find a function and then turn to microscopists to pinpoint the structure responsible for that function. Using this method, Palade, Porter, and Claude entered the luminous heart of the cell. ([Location 1463](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=1463)) - Tags: [[blue]] - The whole process can be imagined as an elaborate postal system. It begins with the linguistic code of genes (RNA) that is translated to write the letter (the protein). The protein is written, or synthesized, by the cell’s letter writer (the ribosome), which then posts it to the mailbox (the pore by which the protein enters the ER). The pore routes it to the central posting station (the endoplasmic reticulum), which then sends the letter to the sorting system (the Golgi), and finally brings it to the delivery vehicle (the secretory granule). There are, in fact, even codes appended to proteins (stamps) that enable the cell to determine their ultimate destination. This “postal system,” Palade realized, is how most proteins get to their correct locations within the cell. ([Location 1490](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=1490)) - Tags: [[blue]] - Plant cells contain structures called chloroplasts, the sites of photosynthesis, the conversion of light into glucose. Chloroplasts, like mitochondria, carry their own DNA, again suggesting an origin in microbes that were engulfed by other cells. ([Location 1506](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=1506)) - Tags: [[blue]] - If a single cell’s DNA could be stretched out straight, like a wire, it would measure six and a half feet. And if you could do that for every cell in the human body and laid all of that DNA end to end, it would stretch from the Earth to the sun and back again more than sixty times. String together all the DNA in every human being on the planet, and it would reach the Andromeda galaxy and back nearly two and half times. ([Location 1522](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=1522)) - Tags: [[blue]] - Scientists studying the nucleus believe that it contains its own skeleton made of molecular fibers. Proteins, traversing the cytoplasm, enter through the pores of the nuclear membrane and bind to the DNA and turn genes on and off. Hormones, bound to proteins, traffic in and out. ATP, the universal source of energy, moves swiftly through the pores. ([Location 1526](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=1526)) - Tags: [[blue]] - When a cell divides, every chromosome is copied, and the two copies separate in space. In human cells, the nuclear envelope dissolves, one full set of chromosomes migrates to each of the two newborn daughter cells, and the nuclear membrane reappears around them—in essence, regenerating a daughter cell with a new nucleus and chromosomes lodged inside it. ([Location 1531](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=1531)) - Tags: [[blue]] - a cell’s autonomy lies in its anatomy. And that autonomy, in turn, enables an essential feature of living systems: the capacity to maintain the fixity of an internal milieu—a phenomenon termed “homeostasis.” ([Location 1542](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=1542)) - Tags: [[blue]] - Bernard inverted that logic. “La fixité du milieu intérieur est la condition de la vie libre, indépendante”: the constancy of the interior environment is the condition of free and independent life, Bernard wrote in 1878. In shifting physiology’s focus from action to the maintenance of fixity, Bernard changed our conception of how an organism’s body works. A major point of physiological “activity,” paradoxically, was to enable stasis. Don’t just do something, stand there ([Location 1548](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=1548)) - Tags: [[blue]] - The discovery of functional anatomy enabled an integrated view of the cell and, by extension, of the defining features of life. A cell, as noted before, is not just a system of parts sitting next to parts, just as a car is not a carburetor sitting next to an engine. It is an integrating machine that must amalgamate the functions of these individual parts to enable the fundamental features of life. Between 1940 and 1960, scientists began to integrate the separate parts of the cell to understand how an autonomous living unit might function and become “living.” ([Location 1568](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=1568)) - Tags: [[blue]] - In the 1950s and 1960s, medicine and surgery witnessed an explosion of organ-directed therapies: rerouting blood vessels in a heart to bypass a blockage, or replacing a diseased kidney with a transplanted organ. A new universe of drugs emerged—antibiotics, antibodies, chemicals to prevent blood clots or reduce cholesterol. But this is organelle-directed therapy: the replenishment of a functional deficiency in the mitochondrion of a retinal ganglion cell. It represents the culmination of decades of study of cellular anatomy, the dissection of subcellular compartments, and the characterization of their dysfunction in diseased states. It is gene therapy, of course, but also cell therapy in situ—in other words, the restoration of function of a diseased cell in its native anatomical location in the human body. ([Location 1628](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=1628)) - Tags: [[blue]] - Conceptually speaking, cell division in animals might be broadly divided into two purposes or functions: production and reproduction. By production, I mean the creation of new cells to build, grow, or repair an organism. When skin cells divide to heal a wound, when T cells divide to produce an immune response, the cells are giving birth to new cells either to produce a tissue or an organ, or to fulfill a function. But it is a completely different matter when sperm or eggs are generated in the human body. Here they are being generated to undergo reproduction—dividing to produce not a new function or an organ but rather a new organism. ([Location 1682](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=1682)) - Tags: [[blue]] - In humans and multicellular organisms, the process for the production of new cells to build organs and tissues is called mitosis—from mitos, the Greek word for “thread.” In contrast, the birth of new cells, sperm, and eggs for the purpose of reproduction—to make a new organism—is called meiosis, from meion, the Greek word for “lessening.” ([Location 1686](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=1686)) - Tags: [[blue]] - The scheme, he found, was startlingly systematic.II It was staged as precisely as a military drill. In the larvae of salamanders—in the dividing cells of mammals, amphibians, and fish—Flemming found a common rhythm of cell division that ran through virtually every organism. It was an exhilarating result: no scientist before him had even faintly imagined that the cells of such diverse organisms would follow a nearly identical and rhythmic scheme during the division of their cells. The first step, Flemming found, was the condensation of the threadlike chromosomes into thickened bundles—“skeins,” he called them. The dye now bound strongly; the chromosomes glowed under the scope, like reels of thread dyed with deep indigo. Then the condensed chromosomes doubled and split along a defined axis, creating structures that reminded him of two starbursts splitting. The “nuclear figures began to organize themselves into successive stages during division,” he wrote. The nuclear membrane dissolved, and the nucleus, too, began to split. At last, the cell itself divided, its membrane segmented, giving rise to two daughter cells. Once in the daughter cells, the chromosomes uncondensed slowly and returned to their wispy “resting stage,” back in the nuclei of the daughter cells—as if reversing the process that had initiated cell division. Since the chromosomes doubled at first and then halved upon cell division, the number of chromosomes in the daughter cells was conserved. Forty-six became ninety-two, and was halved to forty-six. Flemming called it homotypic, or “conservative,” cell division: the parent cell and the daughter cells ended up with the same, conserved number of chromosomes.III Between the 1880s and the early 1900s, the biologists Theodor Boveri, Oscar Hertwig, and Edmund Wilson would contribute a great many details to this initial sketch of cell division, delving further into each of the individual steps that Flemming had initially described. ([Location 1707](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=1707)) - Tags: [[blue]] - The genesis of sperm and eggs, then, must require first halving the number of chromosomes, twenty-three each, and then restoring them back to forty-six upon fertilization. ([Location 1736](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=1736)) - Tags: [[blue]] - cells that opt out of the cycle altogether. They are permanently or semipermanently resting—quiescent, to use biology jargon. This phase is now termed G-zero, the G0 referring to the “gap,” or resting cycle. In fact, some of these cells will never divide; they are post-mitotic. Most mature neurons are good examples. ([Location 1750](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=1750)) - The phase that follows Gap 1 is distinct and unique: the duplication of chromosomes—and therefore, the synthesis of new DNA. It demands energy, commitment, and a drastic shift in focus. It is termed the S phase, from synthesis—synthesis of duplicate chromosomes. If you inhabited the interior of the cell, swimming, as you once were, in the protoplasm, you might sense a shift in its hub of activity away from the cytoplasm and toward the nucleus. Enzymes that duplicate DNA latch on to chromosomes. Yet other enzymes begin to unwind DNA. The building blocks of DNA are shuttled to the nucleus. A complex assemblage of DNA-replicating enzymes strings along the chromosomes, synthesizing a duplicate copy. And an apparatus to pull the duplicated chromosomes apart begins to form within the cell. ([Location 1758](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=1758)) - It was an old biological trick: disrupting a physiological function in order to illuminate normal physiology. An anatomist might cut, or ligate, an artery in an animal and then track the body part that was no longer perfused and thereby learn the artery’s function. Or a geneticist might mutate a gene to disrupt a genetic process—cell division, for example—and thereby uncover the functional master regulators that govern the process of mitosis. ([Location 1795](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=1795)) - Nurse and Hartwell, meanwhile, were also closing in on the cell cycle controlling genes using their mutant-hunting approach in yeast cells. They, too, had found several genes associated with different phases of cell division. In the late 1980s, they named these cdc, and later cdk, genes.V The proteins encoded by them were called CDK proteins. ([Location 1822](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=1822)) - A particular Cyclin protein, we now know, binds to a particular CDK protein, and activates it. That activation, in turn, unleashes a cascade of molecular events in the cell—pinging from one activated molecule to another, like a pinball—that ultimately “commands” the cell to transition from one phase of the cell cycle to the next. Hunt had solved half the puzzle; Nurse and Hartwell had solved the other half. ([Location 1833](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=1833)) - The fact that only about one-third of single-cell embryos form blastocysts reflects the one-third success rate of IVF that is found clinically. By playing the film backward, and using software to measure various parameters, the Stanford group identified just three factors that were predictive of future blastocyst formation: the duration of time that it takes the first cell to divide for the first time; the time between that first division and the second; and the synchronicity of the second and third mitosis. By relying on this trio of parameters, the odds of predicting blastocyst formation (and, subsequently, the chance of viable implantation) increased to 93 percent. Imagine IVF performed with a single embryo—no high-risk pregnancies with twins and triplets—and with a 90 percent success rate. ([Location 2044](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=2044)) - perhaps the most astonishing feature of multicellularity is that it evolved independently, and in multiple different species, not just once, but many, many times. It is as if the drive to become multicellular was so forceful and pervasive that evolution leapt over the fence again and again. Genetic evidence suggests this incontrovertibly. Collective existence—above isolation—was so selectively advantageous that the forces of natural selection gravitated repeatedly toward the collective. The transformation from single cells into multicellularity was, as the evolutionary biologists Richard Grosberg and Richard Strathmann wrote, a “minor major transition.” ([Location 2303](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=2303)) - Tags: [[blue]] - first, the propagation of the multicellular clusters was driven by physical constraints: the snowflakeys had grown so big that they were forced to split by the physical strain caused by their size. But then there was an additional surprise: as the clusters kept evolving, a subset of cells in the middle committed a form of deliberate, programmed suicide, thereby enabling a cleft—a cleavage line, a furrow—between the two aggregates, enabling detachment of one cluster from the mother. ([Location 2343](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=2343)) - Tags: [[blue]] - We can only generate theories and lab experiments about why single cells are so singularly drawn to form multicellular clusters. To see the real forces of natural selection in action, we would need to rewind time. But the reigning theories suggest that specialization and cooperativity conserve energy and resources while allowing new, synergistic functions to develop. One part of the collective can handle waste disposal, for instance, while another acquires food—and thus the multicellular cluster acquires an evolutionary edge. One prominent hypothesis, bolstered by experiments and mathematical modeling, suggests that multicellularity evolved to support larger sizes and rapid movement, thereby enabling the organism to escape predation (it’s hard to swallow a snowflake-sized body) or to make faster, coordinated movements toward weak gradients of food. Evolution raced toward collective existence because “organisms” could race away from being eaten—or, equally, race toward eating. The answer may be unknowable, or perhaps there are many answers. What we do know is that the evolution of multicellularity was not an accident, but purposeful and directional. As I described above in Ratcliff’s yeast experiment, certain cells acquire the ability to perform a programmed form of cell death, or self-sacrifice, to split one cluster from another—a sign of cellular specialization at particular, defined locations. And as Ratcliff has found, as his multicellular aggregates grow generation upon generation, they may be in the process of developing channels to deliver nutrients into the depths of their anatomy. ([Location 2357](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=2357)) - Tags: [[blue]] - For the German poet Johann Wolfgang von Goethe, the serial—and miraculous—metamorphosis of an embryonic form into a mature organism was a sign of Nature at “play.” “It is becoming aware of the form with which Nature, so to speak, always plays,” he wrote in 1786, “and playing brings forth manifold life.” The fetus did not passively balloon into life; Nature “played” with the early forms of an embryo, as a child might play with clay—molding it, sculpting it—into the form of a mature organism. ([Location 2427](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=2427)) - embryologists have come to discover that the process is even more complex. There is an interplay between intrinsic signals, encoded by genes within cells, and extrinsic signals induced by surrounding cells. The extrinsic signals (proteins and chemicals) reach the recipient cells and activate or repress genes in them. They also interact with one another: cancelling or amplifying their actions, ultimately leading cells to adopt their fates, positions, connections, and locations. ([Location 2498](https://readwise.io/to_kindle?action=open&asin=B09RX45W14&location=2498))