# The Gene  ## Metadata - Author: [[Siddhartha Mukherjee]] - Full Title: The Gene - Category: #books ## Highlights - While my family’s history of mental illness was cutting through my consciousness like a red line, my scientific work as a cancer biologist was also converging on the normalcy and abnormalcy of genes. Cancer, perhaps, is an ultimate perversion of genetics—a genome that becomes pathologically obsessed with replicating itself. The genome-as-self-replicating-machine co-opts the physiology of a cell, resulting in a shape-shifting illness that, despite significant advances, still defies our ability to treat or cure it. ([Location 222](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=222)) - Three profoundly destabilizing scientific ideas ricochet through the twentieth century, trisecting it into three unequal parts: the atom, the byte, the gene. Each is foreshadowed by an earlier century, but dazzles into full prominence in the twentieth. Each begins its life as a rather abstract scientific concept, but grows to invade multiple human discourses—thereby transforming culture, society, politics, and language. But the most crucial parallel between the three ideas, by far, is conceptual: each represents the irreducible unit—the building block, the basic organizational unit—of a larger whole: the atom, of matter; the byte (or “bit”), of digitized information; the gene, of heredity and biological information. ([Location 234](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=234)) - The atom, the byte, and the gene provide fundamentally new scientific and technological understandings of their respective systems. You cannot explain the behavior of matter—why gold gleams; why hydrogen combusts with oxygen—without invoking the atomic nature of matter. Nor can you understand the complexities of computing—the nature of algorithms, or the storage or corruption of data—without comprehending the structural anatomy of digitized information. “Alchemy could not become chemistry until its fundamental units were discovered,” a nineteenth-century scientist wrote. By the same token, as I argue in this book, it is impossible to understand organismal and cellular biology or evolution—or human pathology, behavior, temperament, illness, race, and identity or fate—without first reckoning with the concept of the gene. ([Location 249](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=249)) - The atom provides an organizing principle for modern physics—and it tantalizes us with the prospect of controlling matter and energy. The gene provides an organizing principle for modern biology—and it tantalizes us with the prospect of controlling our bodies and fates. ([Location 284](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=284)) - The “action” of a gene is described in mechanistic terms: genes encode chemical messages to build proteins that ultimately enable form and function. ([Location 294](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=294)) - A century after Pythagoras’s death, Plato, writing in 380 BC, was captivated by this metaphor. In one of the most intriguing passages in The Republic—borrowed, in part, from Pythagoras—Plato argued that if children were the arithmetic derivatives of their parents, then, at least in principle, the formula could be hacked: perfect children could be derived from perfect combinations of parents breeding at perfectly calibrated times. A “theorem” of heredity existed; it was merely waiting to be known. By unlocking the theorem and then enforcing its prescriptive combinations, any society could guarantee the production of the fittest children—unleashing a sort of numerological eugenics: “For when your guardians are ignorant of the law of births, and unite bride and bridegroom out of season, the children will not be goodly or fortunate,” Plato concluded. The guardians of his republic, its elite ruling class, having deciphered the “law of births,” would ensure that only such harmonious “fortunate” unions would occur in the future. A political utopia would develop as a consequence of genetic utopia. ([Location 435](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=435)) - Aristotle offered an alternative theory that was strikingly radical for its time: perhaps females, like males, contribute actual material to the fetus—a form of female semen. And perhaps the fetus is formed by the mutual contributions of male and female parts. Grasping for analogies, Aristotle called the male contribution a “principle of movement.” “Movement,” here, was not literally motion, but instruction, or information—code, to use a modern formulation. The actual material exchanged during intercourse was merely a stand-in for a more obscure and mysterious exchange. Matter, in fact, didn’t really matter; what passed from man to woman was not matter, but message. Like an architectural plan for a building, or like a carpenter’s handiwork to a piece of wood, male semen carried the instructions to build a child. “[Just as] no material part comes from the carpenter to the wood in which he works,” Aristotle wrote, “but the shape and the form are imparted from him to the material by means of the motion he sets up. . . . In like manner, Nature uses the semen as a tool.” ([Location 464](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=464)) - Aristotle was wrong in his partitioning of male and female contributions into “material” and “message,” but abstractly, he had captured one of the essential truths about the nature of heredity. The transmission of heredity, as Aristotle perceived it, was essentially the transmission of information. Information was then used to build an organism from scratch: message became material. And when an organism matured, it generated male or female semen again—transforming material back to message. In fact, rather than Pythagoras’s triangle, there was a circle, or a cycle, at work: form begat information, and then information begat form. Centuries later, the biologist Max Delbrück would joke that Aristotle should have been given the Nobel Prize posthumously—for the discovery of DNA. ([Location 476](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=476)) - Darwin’s interest ranged far beyond theology. Holed up in a room above a tobacconist’s shop on Sidney Street, he had occupied himself by collecting beetles, studying botany and geology, learning geometry and physics, and arguing hotly about God, divine intervention, and the creation of animals. More than theology or philosophy, Darwin was drawn to natural history—the study of the natural world using systematic scientific principles. ([Location 543](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=543)) - It was this static view of nature that Darwin found troubling. A natural historian should be able to describe the state of the natural world in terms of causes and effects, Darwin reasoned—just as a physicist might describe the motion of a ball in the air. The essence of Darwin’s disruptive genius was his ability to think about nature not as fact—but as process, as progression, as history. It was a quality that he shared with Mendel. Both obsessive observers of the natural world, Darwin and Mendel made their crucial leaps by asking variants of the same question: How does “nature” come into being? Mendel’s question was microscopic: How does a single organism transmit information to its offspring over a single generation? Darwin’s question was macroscopic: How do organisms transmute information about their features over a thousand generations? In time, both visions would converge, giving rise to the most important synthesis in modern biology, and the most powerful understanding of human heredity. ([Location 587](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=587)) - On October 20, Darwin returned to sea, headed toward Tahiti. Back in his room aboard the Beagle, he began to systematically analyze the corpses of the birds that he had collected. The mockingbirds, in particular, surprised him. There were two or three varieties, but each subtype was markedly distinct, and each was endemic to one particular island. Offhandedly, he scribbled one of the most important scientific sentences that he would ever write: “Each variety is constant in its own Island.” Was the same pattern true of other animals—of the tortoises, say? Did each island have a unique tortoise type? He tried, belatedly, to establish the same pattern for the turtles—but it was too late. He and the crew had eaten the specimens for lunch. ([Location 630](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=630)) - while Owen, Gould, and Lyell named and classified the South American treasures, Darwin turned his mind to other problems. He was not a splitter, but a lumper, a seeker of deeper anatomy. Taxonomy and nomenclature were, for him, merely means to an end. His instinctive genius lay in unearthing patterns—systems of organization—that lay behind the specimens; not in Kingdoms and Orders, but in kingdoms of order that ran through the biological world. ([Location 641](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=641)) - Already, the bare outline of an idea was coalescing in his mind—a notion so simple, and yet so deeply radical, that no biologist had dared to explore it fully: What if all the finches had arisen from a common ancestral finch? What if the small armadillos of today had arisen from a giant ancestral armadillo? Lyell had argued that the current landscape of the earth was the consequence of natural forces that had accumulated over millions of years. In 1796, the French physicist Pierre-Simon Laplace had proposed that even the current solar system had arisen from the gradual cooling and condensation of matter over millions of years (when Napoléon had asked Laplace why God was so conspicuously missing from his theory, Laplace had replied with epic cheekiness: “Sire, I had no need for that hypothesis”). What if the current forms of animals were also the consequence of natural forces that had accumulated over millennia? ([Location 657](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=657)) - In Malthus’s paper, Darwin immediately saw a solution to his quandary. This struggle for survival was the shaping hand. Death was nature’s culler, its grim shaper. “It at once struck me,” he wrote, “that under these circumstances [of natural selection], favourable variations would tend to be preserved and unfavourable ones to be destroyed. The results of this would be the formation of a new species.”I ([Location 698](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=698)) - Darwin now had the skeletal sketch of his master theory. When animals reproduce, they produce variants that differ from the parents.II Individuals within a species are constantly competing for scarce resources. When these resources form a critical bottleneck—during a famine, for instance—a variant better adapted for an environment is “naturally selected.” The best adapted—the “fittest”—survive (the phrase survival of the fittest was borrowed from the Malthusian economist Herbert Spencer). These survivors then reproduce to make more of their kind, thereby driving evolutionary change within a species. ([Location 702](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=702)) - As new Malthusian limits were imposed—diseases, famines, parasites—new breeds gained a stronghold, and the population shifted again. Freaks became norms, and norms became extinct. Monster by monster, evolution advanced. ([Location 712](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=712)) - Darwin tried to envision a theory of heredity that would be compatible with evolution. But here his crucial intellectual shortcoming came to the fore: he was not a particularly gifted experimentalist. Mendel, as we shall see, was an instinctual gardener—a breeder of plants, a counter of seeds, an isolator of traits; Darwin was a garden digger—a classifier of plants, an organizer of specimens, a taxonomist. Mendel’s gift was experimentation—the manipulation of organisms, cross-fertilization of carefully selected sub-breeds, the testing of hypotheses. Darwin’s gift was natural history—the reconstruction of history by observing nature. Mendel, the monk, was an isolator; Darwin, who had once aspired to be a parson, a synthesizer. ([Location 796](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=796)) - Jenkin’s central problem with Darwin was this: if hereditary traits kept “blending” with each other in every generation, then what would keep any variation from being diluted out immediately by interbreeding? “The [variant] will be swamped by the numbers,” Jenkin wrote, “and after a few generations its peculiarity will be obliterated.” As an example—colored deeply by the casual racism of his era—Jenkin concocted a story: “Suppose a white man to have been wrecked on an island inhabited by negroes. . . . Our shipwrecked hero would probably become king; he would kill a great many blacks in the struggle for existence; he would have a great many wives and children.” But if genes blended with each other, then Jenkin’s “white man” was fundamentally doomed—at least in a genetic sense. His children—from black wives—would presumably inherit half his genetic essence. His grandchildren would inherit a quarter; his great-grandchildren, an eighth; his great-great-grandchildren, one-sixteenth, and so forth—until his genetic essence had been diluted, in just a few generations, into complete oblivion. Even if “white genes” were the most superior—the “fittest,” to use Darwin’s terminology—nothing would protect them from the inevitable decay caused by blending. In the end, the lone white king of the island would vanish from its genetic history—even though he had fathered more children than any other man of his generation, and even though his genes were best suited for survival. The particular details of Jenkin’s story were ugly—perhaps deliberately so—but its conceptual point was clear. If heredity had no means of maintaining variance—of “fixing” the altered trait—then all alterations in characters would eventually vanish into colorless oblivion by virtue of blending. Freaks would always remain freaks—unless they could guarantee the passage of their traits to the next generation. ([Location 827](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=827)) - Darwin was deeply struck by Jenkin’s reasoning. “Fleeming Jenkins [sic] has given me much trouble,” he wrote, “but has been of more use to me than any other Essay or Review.” There was no denying Jenkin’s inescapable logic: to salvage Darwin’s theory of evolution, he needed a congruent theory of heredity. But what features of heredity might solve Darwin’s problem? For Darwinian evolution to work, the mechanism of inheritance had to possess an intrinsic capacity to conserve information without becoming diluted or dispersed. Blending would not work. There had to be atoms of information—discrete, insoluble, indelible particles—moving from parent to child. ([Location 849](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=849)) - “How small a thought it takes to fill someone’s whole life,” the philosopher Ludwig Wittgenstein wrote. Indeed, at first glance, Mendel’s life seemed to be filled with the smallest thoughts. Sow, pollinate, bloom, pluck, shell, count, repeat. The process was excruciatingly dull—but small thoughts, Mendel knew, often bloomed into large principles. If the powerful scientific revolution that had swept through Europe in the eighteenth century had one legacy, it was this: the laws that ran through nature were uniform and pervasive. The force that drove Newton’s apple from the branch to his head was the same force that guided planets along their celestial orbits. If heredity too had a universal natural law, then it was likely influencing the genesis of peas as much as the genesis of humans. ([Location 920](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=920)) - But where had the recessive trait disappeared? Had it been consumed or eliminated by the dominant allele? Mendel deepened his analysis with his second experiment. He bred short-tall hybrids with short-tall hybrids to produce third-generation progeny. Since tallness was dominant, all the parental plants in this experiment were tall to start; the recessive trait had disappeared. But when crossed with each other, Mendel found, they yielded an entirely unexpected result. In some of these third-generation crosses, shortness reappeared—perfectly intact—after having disappeared for a generation. ([Location 938](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=938)) - A “hybrid” organism, Mendel realized, was actually a composite—with a visible, dominant allele and a latent, recessive allele ([Location 943](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=943)) - Heredity, Mendel’s experiments implied, could only be explained by the passage of discrete pieces of information from parents to offspring. Sperm brought one copy of this information (an allele); the egg brought the other copy (a second allele); an organism thus inherited one allele from each parent. When that organism generated sperm or eggs, the alleles were split up again—one was passed to the sperm, and one to the egg, only to become combined in the next generation. One allele might “dominate” the other when both were present. When the dominant allele was present, the recessive allele seemed to disappear, but when a plant received two recessive alleles, the allele reiterated its character. Throughout, the information carried by an individual allele remained indivisible. The particles themselves remained intact. ([Location 961](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=961)) - In the summer of 1878, a thirty-year-old Dutch botanist named Hugo de Vries traveled to England to see Darwin. It was more of a pilgrimage than a scientific visit. Darwin was vacationing at his sister’s estate in Dorking, but de Vries tracked him down and traveled out to meet him. Gaunt, intense, and excitable, with Rasputin’s piercing eyes and a beard that rivaled Darwin’s, de Vries already looked like a younger version of his idol. He also had Darwin’s persistence. The meeting must have been exhausting, for it lasted only two hours, and Darwin had to excuse himself to take a break. But de Vries left England transformed. With no more than a brief conversation, Darwin had inserted a sluice into de Vries’s darting mind, diverting it forever. Back in Amsterdam, de Vries abruptly terminated his prior work on the movement of tendrils in plants and threw himself into solving the mystery of heredity. ([Location 1035](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=1035)) - Tags: [[blue]] - Weismann had proposed a radical alternative: perhaps hereditary information was contained exclusively in sperm and egg cells, with no direct mechanism for an acquired characteristic to be transmitted into sperm or eggs. No matter how ardently the giraffe’s ancestor stretched its neck, it could not convey that information into its genetic material. Weismann called this hereditary material germplasm and argued that it was the only method by which an organism could generate another organism. Indeed, all of evolution could be perceived as the vertical transfer of germplasm from one generation to the next: an egg was the only way for a chicken to transfer information to another chicken. ([Location 1060](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=1060)) - Tags: [[blue]] - In his experimental gardens in Munich and Tübingen, about four hundred miles from the abbey, Correns thus laboriously bred tall plants with short plants and made hybrid-hybrid crosses—with no knowledge that he was just methodically repeating Mendel’s prior work. When Correns completed his experiments and was ready to assemble his paper for publication, he returned to the library to find references to his scientific predecessors. He thus stumbled on Mendel’s earlier paper buried in the Brno journal. ([Location 1095](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=1095)) - Tags: [[blue]] - But de Vries also took his experiments further than Mendel. He may have been preempted in the discovery of heritable units—but as de Vries delved more deeply into heredity and evolution, he was struck by a thought that must also have perplexed Mendel: How did variants arise in the first place? What force made tall versus short peas, or purple flowers and white ones? ([Location 1111](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=1111)) - Tags: [[blue]] - De Vries quickly realized the importance of his observation: these mutants had to be the missing pieces in Darwin’s puzzle. Indeed, if you coupled the genesis of spontaneous mutants—the giant-leaved Oenothera, say—with natural selection, then Darwin’s relentless engine was automatically set in motion. Mutations created variants in nature: long-necked antelopes, short-beaked finches, and giant-leaved plants arose spontaneously in the vast tribes of normal specimens (contrary to Lamarck, these mutants were not generated purposefully, but by random chance). These variant qualities were hereditary—carried as discrete instructions in sperm and eggs. As animals struggled to survive, the best-adapted variants—the fittest mutations—were serially selected. Their children inherited these mutations and thus generated new species, thereby driving evolution. Natural selection was not operating on organisms but on their units of heredity. A chicken, de Vries realized, was merely an egg’s way of making a better egg. ([Location 1122](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=1122)) - Tags: [[blue]] - More than any scientist before him, Bateson also grasped the idea that the discontinuous nature of genetic information carried vast implications for the future of human genetics. If genes were, indeed, independent particles of information, then it should be possible to select, purify, and manipulate these particles independently from one another. Genes for “desirable” attributes might be selected or augmented, while undesirable genes might be eliminated from the gene pool. In principle, a scientist should be able to change the “composition of individuals,” and of nations, and leave a permanent mark on human identity. “When power is discovered, man always turns to it,” Bateson wrote darkly. “The science of heredity will soon provide power on a stupendous scale; and in some country, at some time not, perhaps, far distant, that power will be applied to control the composition of a nation. Whether the institution of such control will ultimately be good or bad for that nation, or for humanity at large, is a separate question.” He had preempted the century of the gene. ([Location 1156](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=1156)) - Tags: [[blue]] - Improved environment and education may better the generation already born. Improved blood will better every generation to come. —Herbert Walter, Genetics ([Location 1169](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=1169)) - Tags: [[blue]] - In 1883, one year after Charles Darwin’s death, Darwin’s cousin Francis Galton published a provocative book—Inquiries into Human Faculty and Its Development—in which he laid out a strategic plan for the improvement of the human race. Galton’s idea was simple: he would mimic the mechanism of natural selection. If nature could achieve such remarkable effects on animal populations through survival and selection, Galton imagined accelerating the process of refining humans via human intervention. The selective breeding of the strongest, smartest, “fittest” humans—unnatural selection—Galton imagined, could achieve over just a few decades what nature had been attempting for eons. Galton needed a word for this strategy. “We greatly want a brief word to express the science of improving stock,” he wrote, “to give the more suitable races or strains of blood a better chance of prevailing speedily over the less suitable.” For Galton, the word eugenics was an opportune fit—“at least a neater word . . . than viriculture, which I once ventured to use.” It combined the Greek prefix eu—“good”—with genesis: “good in stock, hereditarily endowed with noble qualities.” Galton—who never blanched from the recognition of his own genius—was deeply satisfied with his coinage: “Believing, as I do, that human eugenics will become recognised before long as a study of the highest practical importance, it seems to me that no time ought to be lost in . . . compiling personal and family histories.” ([Location 1175](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=1175)) - Tags: [[blue]] - Like Fleeming Jenkin, Galton quickly realized that his cousin had got the principle right, but not the mechanism: the nature of inheritance was crucial to the understanding of Darwin’s theory. Heredity was the yin to evolution’s yang. The two theories had to be congenitally linked—each bolstering and completing the other. If “cousin Darwin” had solved half the puzzle, then “cousin Galton” was destined to crack the other. ([Location 1201](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=1201)) - Tags: [[blue]] - Bateson’s “awakening” was not private in the least. Between 1900 and 1910, as evidence for Mendel’s “units of heredity” mounted, biologists were confronted by the impact of the new theory. The implications were deep. Aristotle had recast heredity as the flow of information—a river of code moving from egg to the embryo. Centuries later, Mendel had stumbled on the essential structure of that information, the alphabet of the code. If Aristotle had described a current of information moving across generations, then Mendel had found its currency. But perhaps an even greater principle was at stake, Bateson realized. The flow of biological information was not restricted to heredity. It was coursing through all of biology. The transmission of hereditary traits was just one instance of information flow—but if you looked deeply, squinting your conceptual lenses, it was easy to imagine information moving pervasively through the entire living world. The unfurling of an embryo; the reach of a plant toward sunlight; the ritual dance of bees—every biological activity required the decoding of coded instructions. Might Mendel, then, have also stumbled on the essential structure of these instructions? Were units of information guiding each of these processes? “Each of us who now looks at his own patch of work sees Mendel’s clues running through it,” Bateson proposed. “We have only touched the edge of that new country which is stretching out before us. . . . The experimental study of heredity . . . is second to no branch of science in the magnitude of the results it offers.” ([Location 1281](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=1281)) - Tags: [[blue]] - But in science, a word is a hypothesis. In natural language, a word is used to convey an idea. But in scientific language, a word conveys more than an idea—a mechanism, a consequence, a prediction. A scientific noun can launch a thousand questions—and the idea of the “gene” did exactly that. What was the chemical and physical nature of the gene? How was the set of genetic instructions, the genotype, translated into the actual physical manifestations, the phenotype, of an organism? How were genes transmitted? Where did they reside? How were they regulated? If genes were discrete particles specifying one trait, then how could this property be reconciled with the occurrence of human characteristics, say, height or skin color, in continuous curves? How does the gene permit genesis? ([Location 1306](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=1306)) - Tags: [[blue]] - Galton and his friends were chilled by the fear of race degeneration (Galton’s own encounter with the “savage races,” symptomatic of Britain’s encounter with colonial natives throughout the seventeenth and eighteenth centuries, had also convinced him that the racial purity of whites had to be maintained and protected against the forces of miscegenation). The Second Reform Act of 1867 had given working-class men in Britain the right to vote. By 1906, even the best-guarded political bastions had been stormed—twenty-nine seats in Parliament had fallen to the Labour Party—sending spasms of anxiety through English high society. The political empowerment of the working class, Galton believed, would just provoke their genetic empowerment: they would produce bushels of children, dominate the gene pool, and drag the nation toward profound mediocrity. The homme moyen would degenerate. The “mean man” would become even meaner. ([Location 1366](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=1366)) - Tags: [[blue]] - Indeed, Wells had only articulated what many in Galton’s inner circle felt deeply but had not dared to utter—that eugenics would only work if the selective breeding of the strong (so-called positive eugenics) was augmented with selective sterilization of the weak—negative eugenics. In 1911, Havelock Ellis, Galton’s colleague, twisted the image of Mendel, the solitary gardener, to service his enthusiasm for sterilization: “In the great garden of life it is not otherwise than in our public gardens. We repress the license of those who, to gratify their own childish or perverted desires, would pluck up the shrubs or trample on the flowers, but in so doing we achieve freedom and joy for all. . . . We seek to cultivate the sense of order, to encourage sympathy and foresight, to pull up racial weeds by the roots. . . . In these matters, indeed, the gardener in his garden is our symbol and our guide.” ([Location 1378](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=1378)) - Tags: [[blue]] - Morgan had discovered an important modification to Mendel’s laws. Genes did not travel separately; instead, they moved in packs. Packets of information were themselves packaged—into chromosomes, and ultimately in cells. But the discovery had a more important consequence: conceptually, Morgan had not just linked genes; he had linked two disciplines—cell biology and genetics. The gene was not a “purely theoretical unit.” It was a material thing that lived in a particular location, and a particular form, within a cell. “Now that we locate them [genes] on chromosomes,” Morgan reasoned, “are we justified in regarding them as material units; as chemical bodies of a higher order than molecules?” ([Location 1685](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=1685)) - Tags: [[blue]] - Scientists studying living organisms were far more preoccupied with other matters: embryology, cell biology, the origin of species, and evolution. How do cells function? How does an organism arise from an embryo? How do species originate? What generates the diversity of the natural world? Yet, attempts to answer these questions had all become mired at precisely the same juncture. The missing link, in all cases, was information. Every cell, and every organism, needs information to carry out its physiological function—but where does that information come from? ([Location 1774](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=1774)) - In 1918, Fisher published his analysis in a paper entitled “The Correlation between Relatives on the Supposition of Mendelian Inheritance.” The title was rambling, but the message was succinct: if you mixed the effects of three to five variant genes on any trait, you could generate nearly perfect continuity in phenotype. “The exact amount of human variability,” he wrote, could be explained by rather obvious extensions of Mendelian genetics. The individual effect of a gene, Fisher argued, was like a dot of a pointillist painting. If you zoomed in close enough, you might see the dots as individual, discrete. But what we observed and experienced in the natural world from afar was an aggregation of dots: pixels merging to form a seamless picture. ([Location 1829](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=1829)) - To explain the intersection of genetics, natural selection, and evolution in formal terms, Dobzhansky resurrected two important words—genotype and phenotype. A genotype is an organism’s genetic composition. It can refer to one gene, a configuration of genes, or even an entire genome. A phenotype, in contrast, refers to an organism’s physical or biological attributes and characteristics—the color of an eye, the shape of a wing, or resistance to hot or cold temperatures. ([Location 1867](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=1867)) - Dobzhansky could now restate the essential truth of Mendel’s discovery—a gene determines a physical feature—by generalizing that idea across multiple genes and multiple features: a genotype determines a phenotype ([Location 1870](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=1870)) - If Dobzhansky had capriciously trimmed the wings of all the flies in one box, he would have affected their phenotypes—the shape of their wings—without ever touching their genes. In other words: genotype + environment = phenotype ([Location 1876](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=1876)) - some genes are activated by external triggers or by random chance. In flies, for instance, a gene that determines the size of a vestigial wing depends on temperature: you cannot predict the shape of the wing based on the fly’s genes or on the environment alone; you need to combine the two pieces of information. For such genes, neither the genotype nor the environment is the sole predictor of outcome: it is the intersection of genes, environment, and chance. ([Location 1878](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=1878)) - So the final modification might be read as: genotype + environment + triggers + chance = phenotype ([Location 1889](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=1889)) - The process of selection, notably, acts on a physical or biological attribute—and the underlying genes are selected passively as a result. A misshapen nose might be the result of a particularly bad day in the ring—i.e., it may have nothing to do with genes—but if a mating contest is judged only by the symmetry of noses, then the bearer of the wrong kind of nose will be eliminated. Even if that bearer possesses multiple other genes that are salubrious in the long run—a gene for tenacity or for withstanding excruciating pain—the entire gamut of these genes will be damned to extinction during the mating contest, all because of that damned nose. Phenotype, in short, drags genotypes behind it, like a cart pulling a horse. ([Location 1896](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=1896)) - By the late 1930s, Dobzhansky began to realize that his understanding of genes, variation, and natural selection had ramifications far beyond biology. The bloody revolution of 1917 that had swept through Russia attempted to erase all individual distinctions to prioritize a collective good. In contrast, a monstrous form of racism that was rising in Europe exaggerated and demonized individual distinctions. In both cases, Dobzhansky noted, the fundamental questions at stake were biological. What defines an individual? How does variation contribute to individuality? What is “good” for a species? ([Location 1920](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=1920)) - Muller was catapulted into international fame by his discovery. The effect of radiation on the mutation rate in flies had two immediate implications. First, genes had to be made of matter. Radiation, after all, is merely energy. Frederick Griffith had made genes move between organisms. Muller had altered genes using energy. A gene, whatever it was, was capable of motion, transmission, and of energy-induced change—properties generally associated with chemical matter. But more than the material nature of the gene, it was the sheer malleability of the genome—that X-rays could make such Silly Putty of genes—that stunned scientists. ([Location 2027](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=2027)) - Amid the voluminous chaff, two contributions stand out. The first was methodological: Nazi scientists advanced the “twin study”—although, characteristically, they soon morphed it into a ghastly form. Twin studies had originated in Francis Galton’s work in the 1890s. Having coined the phrase nature versus nurture, Galton had wondered how a scientist might discern the influence of one over the other. How could one determine if any particular feature—height or intelligence, say—was the product of nature or nurture? How could one unbraid heredity and environment? Galton proposed piggybacking on a natural experiment. Since twins share identical genetic material, he reasoned, any substantial similarities between them could be attributed to genes, while any differences were the consequence of environment. By studying twins, and comparing and contrasting similarities and differences, a geneticist could determine the precise contributions of nature versus nurture to important traits. ([Location 2241](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=2241)) - Like musicians, like mathematicians—like elite athletes—scientists peak early and dwindle fast. It isn’t creativity that fades, but stamina: science is an endurance sport. To produce that single illuminating experiment, a thousand nonilluminating experiments have to be sent into the trash; it is battle between nature and nerve. ([Location 2331](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=2331)) - Life may be chemistry, but it’s a special circumstance of chemistry. Organisms exist not because of reactions that are possible, but because of reactions that are barely possible. Too much reactivity and we would spontaneously combust. Too little, and we would turn cold and die. Proteins enable these barely possible reactions, allowing us to live on the edges of chemical entropy—skating perilously, but never falling in. ([Location 2346](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=2346)) - It is the form of hemoglobin, then, that permits its function. The physical structure of the molecule enables its chemical nature, the chemical nature enables its physiological function, and its physiology ultimately permits its biological activity. The complex workings of living beings can be perceived in terms of these layers: physics enabling chemistry, and chemistry enabling physiology. To Schrödinger’s “What is life?” a biochemist might answer, “If not chemicals.” And what are chemicals—a biophysicist might add—if not molecules of matter? ([Location 2468](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=2468)) - Tags: [[blue]] - biophysicists were intent on restoring a rigidly mechanistic description to biology. Living physiology should be explicable in terms of physics, biophysicists argued—forces, motions, actions, motors, engines, levers, pulleys, clasps. The laws that drove Newton’s apples to the ground should also apply to the growth of the apple tree. Invoking special vital forces or inventing mystical fluids to explain life was unnecessary. Biology was physics. Machina en deus. ([Location 2475](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=2475)) - Tags: [[blue]] - To decipher the structure of DNA, Wilkins had decided to corral a set of biophysical techniques invented in nearby Cambridge—crystallography and X-ray diffraction. To understand the basic outline of this technique, imagine trying to deduce the shape of a minute three-dimensional object—a cube, say. You cannot “see” this cube nor feel its edges—but it shares the one property that all physical objects must possess: it generates shadows. Imagine that you can shine light at the cube from various angles and record the shadows that are formed. Placed directly in front of the light, a cube casts a square shadow. Illuminated obliquely, it forms a diamond. Move the light source again, and the shadow is a trapezoid. The process is almost absurdly laborious—like sculpting a face out of a million silhouettes—but it works: piece by piece, a set of two-dimensional images can be transmuted into a three-dimensional form. X-ray diffraction arises out of analogous principles—the “shadows” are actually the scatters of X-rays generated by a crystal—except to illuminate molecules and generate scatters in the molecular world, one needs the most powerful source of light: X-rays. And there’s a subtler problem: molecules generally refuse to sit still for their portraits. In liquid or gas form, molecules whiz dizzily in space, moving randomly, like particles of dust. Shine light on a million moving cubes and you only get a hazy, moving shadow, a molecular version of television static. The only solution to the problem is ingenious: transform a molecule from a solution to a crystal—and its atoms are instantly locked into position. Now the shadows become regular; the lattices generate ordered and readable silhouettes. By shining X-rays at a crystal, a physicist can decipher its structure in three-dimensional space. At Caltech, two physical chemists, Linus Pauling and Robert Corey, had used this technique to solve the structures of several protein fragments—a feat that would win Pauling the Nobel Prize in 1954. ([Location 2483](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=2483)) - Tags: [[blue]] - The noise that bothered Franklin most was the fuzzy static in the DNA pictures. Wilkins had obtained some highly purified DNA from a Swiss lab and stretched it into thin, uniform fibers. By stringing the fiber along a gap in a stretch of wire—a bent paper clip worked marvelously—he hoped to diffract X-rays and obtain images. But the material had proved difficult to photograph; it generated scattered, fuzzy dots on film. What made a purified molecule so difficult to image? she wondered. Soon, she stumbled on the answer. In its pure state, DNA came in two forms. In the presence of water, the molecule was in one configuration, and as it dried out, it switched to another. As the experimental chamber lost its humidity, the DNA molecules relaxed and tensed—exhaling, inhaling, exhaling, like life itself. The switch between the two forms was partly responsible for the noise that Wilkins had been struggling to minimize. Franklin adjusted the humidity of the chamber using an ingenious apparatus that bubbled hydrogen through salt water. As she increased the wetness of DNA in the chamber, the fibers seemed to relax permanently. She had tamed them at last. Within weeks, she was taking pictures of DNA of a quality and clarity that had never before been seen. J. D. Bernal, the crystallographer, would later call them the “most beautiful X ray photographs of any substance ever taken.” ([Location 2527](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=2527)) - Tags: [[blue]] - Watson knew “nothing about the X-ray diffraction technique,” but he had an unfailing intuition about the importance of certain biological problems. Trained as an ornithologist at the University of Chicago, he had assiduously “avoid[ed] taking any chemistry or physics courses which looked of even medium difficulty.” But a kind of homing instinct had led him to DNA. He too had read Schrödinger’s What Is Life? and been captivated. He had been working on the chemistry of nucleic acids in Copenhagen—“a complete flop,” as he would later describe it—but Wilkins’s photograph entranced him. “The fact that I was unable to interpret it did not bother me. It was certainly better to imagine myself becoming famous than maturing into a stifled academic who had never risked a thought.” ([Location 2548](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=2548)) - Tags: [[blue]] - Here, Watson and Crick took their most intuitive scientific leap. What if the solution to the structure of DNA could be achieved by the same “tricks” that Pauling had pulled? X-ray pictures would help, of course—but trying to determine structures of biological molecules using experimental methods, Crick argued, was absurdly laborious—“like trying to determine the structure of a piano by listening to the sound it made while being dropped down a flight of stairs.” But what if the structure of DNA was so simple—so elegant—that it could be deduced by “common sense,” by model building? What if a stick-and-stone assemblage could solve DNA? ([Location 2592](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=2592)) - Tags: [[blue]] - Crick had tried to stabilize the “wobbly unstable chains” by putting the phosphate backbone in the center. But phosphates are negatively charged. If they faced inside the chain, they would repel each other, forcing the molecule to fly apart in a nanosecond. To solve the problem of repulsion, Crick had inserted a positively charged magnesium ion at the center of the helix—like a last-minute dab of molecular glue to hold the structure together. But Franklin’s measurements suggested that magnesium could not be at the center. Worse, the structure modeled by Watson and Crick was so tightly packed that it could not accommodate any significant number of water molecules. In their rush to build a model, they had even forgotten Franklin’s first discovery: the remarkable “wetness” of DNA. ([Location 2639](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=2639)) - Tags: [[blue]] - Note: They looked for confirmation of their model, papering over obviously-wrong structures (like the interior-facing negatively charged phosphate) with quick fixes - In keeping with the grand tradition of counterposing the most significant discoveries in biology with supreme understatement—recall Mendel, Avery, and Griffith—Watson and Crick added a final line to their paper: “It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material.” The most important function of DNA—its capacity to transmit copies of information from cell to cell, and organism to organism—was buried in the structure. Message; movement; information; form; Darwin; Mendel; Morgan: all was writ into that precarious assemblage of molecules. ([Location 2762](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=2762)) - Tags: [[blue]] - But if a mutation disrupts the function of an enzyme, then the normal gene must specify the information to make the normal enzyme. A unit of heredity must carry the code to build a metabolic or cellular function specified by a protein. “A gene,” Beadle wrote in 1945, “can be visualized as directing the final configuration of a protein molecule.” This was the “action of the gene” that a generation of biologists had been trying to comprehend: a gene “acts” by encoding information to build a protein, and the protein actualizes the form or function of the organism. ([Location 2847](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=2847)) - Brenner and Jacob finally purified a minuscule amount of the messenger molecule out of bacterial cells. It was RNA, as expected—but RNA of a special kind.II The messenger was generated afresh when a gene was translated. Like DNA, these RNA molecules were built by stringing together four bases—A, G, C, and U (in the RNA copy of a gene, remember, the T found in DNA is substituted for U). Notably, Brenner and Jacob later discovered the messenger RNA was a facsimile of the DNA chain—a copy made from the original. The RNA copy of a gene then moved from the nucleus to the cytosol, where its message was decoded to build a protein. The messenger RNA was neither an inhabitant of heaven nor of hell—but a professional go-between. The generation of an RNA copy of a gene was termed transcription—referring to the rewriting of a word or sentence in a language close to the original. A gene’s code (ATGGGCC . . .) was transcribed into an RNA code (AUGGGCC . . .). ([Location 2900](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=2900)) - The process was akin to a library of rare books that is accessed for translation. The master copy of information—i.e., the gene—was stored permanently in a deep repository or vault. When a “translation request” was generated by a cell, a photocopy of the original was summoned from the vault of the nucleus. This facsimile of a gene (i.e., RNA) was used as a working source for translation into a protein. The process allowed multiple copies of a gene to be in circulation at the same time, and for the RNA copies to be increased or decreased on demand—facts that would soon prove to be crucial to the understanding of a gene’s activity and function. ([Location 2908](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=2908)) - Francis Crick called this flow of information the “central dogma” of biological information. The word dogma was an odd choice (Crick later admitted that he never understood the linguistic implications of dogma, which implies a fixed, immutable belief)—but the central was an accurate description. Crick was referring to the striking universality of the flow of genetic information throughout biology.IV From bacteria to elephants—from red-eyed flies to blue-blooded princes—biological information flowed through living systems in a systematic, archetypal manner: DNA provided instructions to build RNA. RNA provided instructions to build proteins. Proteins ultimately enabled structure and function—bringing genes to life. ([Location 2941](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=2941)) - It was a Rube Goldberg disease. A change in the sequence of a gene caused the change in the sequence of a protein; that warped its shape; that shrank a cell; that clogged a vein; that jammed the flow; that racked the body (that genes built). Gene, protein, function, and fate were strung in a chain: one chemical alteration in one base pair in DNA was sufficient to “encode” a radical change in human fate. ([Location 2975](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=2975)) - What enabled the selective “action” of hemoglobin in red blood cells? Why was there no hemoglobin in his eye or his skin—even though eye cells and skin cells and, indeed, every cell in the human body possessed identical copies of the same gene? How, as Thomas Morgan had put it, did “the properties implicit in genes become explicit in [different] cells?” ([Location 3007](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=3007)) - By the late 1940s, Monod had discovered that the kink was the result of a metabolic readjustment. When bacteria switched from glucose to lactose consumption, they induced specific lactose-digesting enzymes. When they switched back to glucose, these enzymes disappeared and glucose-digesting enzymes reappeared. The induction of these enzymes during the switch—like changing cutlery between dinner courses (remove the fish knife; set the dessert fork)—took a few minutes, thereby resulting in the observed pause in growth. To Monod, diauxie suggested that genes could be regulated by metabolic inputs. If enzymes—i.e., proteins—were being induced to appear and disappear in a cell, then genes must be being turned on and off, like molecular switches (enzymes, after all, are encoded by genes). ([Location 3036](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=3036)) - As with flies, the bacterial mutants proved revealing. Monod and Jacob, working with Arthur Pardee, a microbial geneticist from America, discovered three cardinal principles that governed the regulation of genes. First, when a gene was turned on or off, the DNA master copy was always kept intact in a cell. The real action was in RNA: when a gene was turned on, it was induced to make more RNA messages and thereby produce more sugar-digesting enzymes. A cell’s metabolic identity—i.e., whether it was consuming lactose or glucose—could be ascertained not by the sequence of its genes, which was always constant, but by the amount of RNA that a gene was producing. During lactose metabolism, the RNAs for lactose-digesting enzymes were abundant. During glucose metabolism, those messages were repressed, and the RNAs for glucose-digesting enzymes became abundant. Second, the production of RNA messages was coordinately regulated. When the sugar source was switched to lactose, the bacteria turned on an entire module of genes—several lactose-metabolizing genes—to digest lactose. One of the genes in the module specified a “transporter protein” that allowed lactose to enter the bacterial cell. Another gene encoded an enzyme that was needed to break down lactose into parts. Yet another specified an enzyme to break those chemical parts into subparts. Surprisingly, all the genes dedicated to a particular metabolic pathway were physically present next to each other on the bacterial chromosome—like library books stacked by subject—and they were induced simultaneously in cells. The metabolic alteration produced a profound genetic alteration in a cell. It wasn’t just a cutlery switch; the whole dinner service was altered in a single swoop. A functional circuit of genes was switched on and off, as if operated by a common spool or a master switch. Monod called one such gene module an operon.II The genesis of proteins was thus perfectly synchronized with the requirements of the environment: supply the correct sugar, and a set of sugar-metabolizing genes would be turned on together. The terrifying economy of evolution had again produced the most elegant solution to gene regulation. No gene, no message, and no protein labored in vain. ([Location 3044](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=3044)) - How did a lactose-sensing protein recognize and regulate only a lactose-digesting gene—and not the thousands of other genes in a cell? The third cardinal feature of gene regulation, Monod and Jacob discovered, was that every gene had specific regulatory DNA sequences appended to it that acted like recognition tags. Once a sugar-sensing protein had detected sugar in the environment, it would recognize one such tag and turn the target genes on or off. That was a gene’s signal to make more RNA messages and thereby generate the relevant enzyme to digest the sugar. A gene, in short, possessed not just information to encode a protein, but also information about when and where to make that protein. All that data was encrypted in DNA, typically appended to the… ([Location 3061](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=3061)) - In Jacob and Monod’s model, in contrast, bacterial genes were strung together for a reason. Genes that operated on the same metabolic pathway were physically linked to each other: if you worked together, then you lived together in the genome. Specific sequences of DNA were appended to a gene that provided context for its activity—its “work.” These sequences, meant to turn genes on and off, might be likened to punctuation marks and annotations—inverted quotes, a comma, a capitalized letter—in a sentence: they… ([Location 3071](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=3071)) - Even though every cell contains the same set of genes—an identical genome—the selective activation or repression of particular subsets of genes allows an individual cell to respond to its environments. The genome was an active blueprint—capable of deploying selected parts of its code at different times and in different circumstances. ([Location 3080](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=3080)) - Proteins act as regulatory sensors, or master switches, in this process—turning on and turning off genes, or even combinations of genes, in a coordinate manner. Like the master score of a bewitchingly complex symphonic work, the genome contains the instructions for the development and maintenance of organisms. But the genomic “score” is inert without proteins. Proteins actualize this information—by activating or repressing genes (some of these regulatory proteins are also called transcription factors). They conduct the genome, thereby playing out its music—activating the viola at the fourteenth minute, a crash of cymbals during the arpeggio, a roll of drums at the crescendo. ([Location 3083](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=3083)) - It was through gene regulation, Monod argued, that cells could achieve their unique functions in time and space. “The genome contains not only a series of blue-prints [i.e., genes], but a co-ordinated program . . . and a means of controlling its execution,” Monod and Jacob concluded. Walter Noel’s red blood cells and liver cells contained the same genetic information—but gene regulation ensured that the hemoglobin protein was only present in red blood cells, and not in the liver. The caterpillar and the butterfly carry precisely the same genome—but gene regulation enables the metamorphosis of one into the other. ([Location 3092](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=3092)) - There is a recursion here that is worth noting: like all proteins, DNA polymerase, the enzyme that enables DNA to replicate, is itself the product of a gene.IV Built into every genome, then, are the codes for proteins that will allow that genome to reproduce. This additional layer of complexity—that DNA encodes a protein that allows DNA to replicate—is important because it provides a critical node for regulation. DNA replication can be turned on and turned off by other signals and regulators, such as the age or the nutritional status of a cell, thus allowing cells to make DNA copies only when they are ready to divide. This scheme has a collateral rub: when the regulators themselves go rogue, nothing can stop a cell from replicating continuously. That, as we will soon learn, is the ultimate disease of malfunctioning genes—cancer. ([Location 3124](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=3124)) - Mutations occur when DNA is damaged by chemicals or X-rays, or when the DNA replication enzyme makes a spontaneous error in copying genes. But a second mechanism of generating genetic diversity exists: genetic information can be swapped between chromosomes. DNA from the maternal chromosome can exchange positions with DNA from the paternal chromosome—potentially generating a gene hybrid of maternal and paternal genes. Recombination is also a form of “mutation”—except whole chunks of genetic material are swapped between chromosomes. ([Location 3142](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=3142)) - When DNA is damaged by a mutagen, such as X-rays, genetic information is obviously threatened. When such damage occurs, the gene can be recopied from the “twin” copy on the paired chromosome: part of the maternal copy may be redrafted from the paternal copy, again resulting in the creation of hybrid genes. ([Location 3152](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=3152)) - A gene, Morgan had noted, was an extraordinary solution to an extraordinary problem. Sexual reproduction demands the collapse of an organism into a single cell, but then requires that single cell to expand back into an organism. The gene, Morgan realized, solves one problem—the transmission of heredity—but creates another: the development of organisms. A single cell must be capable of carrying the entire set of instructions to build an organism from scratch—hence genes. But how do genes make a whole organism grow back out of a single cell? ([Location 3227](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=3227)) - Tags: [[blue]] - The building of organs and structures, Lewis concluded, is encoded by master-regulatory “effector” genes that work like autonomous units or subroutines. During the normal genesis of a fly (or any other organism), these effector genes kick into action at specified sites and at specified times and determine the identities of segments and organs. These master-regulatory genes work by turning other genes on and off; they can be likened to circuits in a microprocessor. Mutations in the genes thus result in malformed, ectopic segments and organs. Like the Red Queen’s bewildered servants in Alice in Wonderland, the genes scurry about to enact the instructions—build a thorax, make a wing—but in the wrong places or at the wrong times. If a master regulator shouts, “ON with an antenna,” then the antenna-building subroutine is turned on and an antenna is built—even if that structure happens to be growing out of the thorax or abdomen of a fly. ([Location 3254](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=3254)) - Tags: [[blue]] - The genes altered in these mutants, Nüsslein-Volhard and Wieschaus reasoned, determine the basic architectural plan of the embryo. They are the mapmakers of the embryonic world. They divide the embryo into its basic subsegments. They then activate Lewis’s commander genes to start building organs and body parts in some (and only those) compartments—an antenna on the head, a wing in the fourth segment of the thorax, and so forth. Nüsslein-Volhard and Wieschaus termed these segmentation genes. But even the segmentation genes have to have their masters: How does the second segment of the fly thorax “know” to be a thoracic segment, and not an abdominal segment? ([Location 3273](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=3273)) - Tags: [[blue]] - In a volley of pathbreaking papers published between 1986 and 1990, Nüsslein-Volhard and her colleagues definitively identified several of the factors that provide the signal for “headness” and “tailness” in the embryo. We now know that about eight such chemicals—mostly proteins—are made by the fly during the development of the egg and deposited asymmetrically in the egg. These maternal factors are made and placed in the egg by the mother fly. The asymmetric deposition is only possible because the egg itself is placed asymmetrically in the mother fly’s body—thereby enabling her to deposit some of these maternal factors on the head end of the egg, and others on the tail end. The proteins create a gradient within the egg. Like sugar diffusing out of a cube in a cup of coffee, they are present at high concentration on one end of the egg, and low concentration on the other. The diffusion of a chemical through a matrix of protein can even create distinct, three-dimensional patterns—like a pool of syrup ribboning into oatmeal. Specific genes are activated at the high-concentration end versus at the low-concentration end, thereby allowing the head-tail axis to be defined, or other patterns to be formed. ([Location 3288](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=3288)) - Tags: [[blue]] - in certain tissues, Kerr noted, dying cells seemed to activate specific structural changes in anticipation of death—as if turning on a “death subroutine.” The dying cells did not elicit gangrene, wounds, or inflammation; they acquired a pearly, wilting translucence, like lilies in a vase before they die. If necrosis was blackening, then this was death by whiteout. Instinctively, Kerr surmised that the two forms of dying were fundamentally different. This “controlled cell deletion,” he wrote, “is an active, inherently programmed phenomenon,” controlled by “genes of death.” Seeking a word to describe the process, he called it apoptosis, an evocative Greek word for the falling off of leaves from trees, or petals from a flower. ([Location 3365](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=3365)) - Tags: [[blue]] - But was the fate of every cell in the worm dictated by genes, and only genes? Horvitz and Sulston discovered occasional cells in the worm—rare pairs—that could choose one fate or another randomly, as if by coin flip. The fate of these cells was not determined by their genetic destiny, but by their proximity to other cells. Two worm biologists working in Colorado, David Hirsh and Judith Kimble, called this phenomenon natural ambiguity. ([Location 3387](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=3387)) - Tags: [[blue]] - A worm was thus constructed from two kinds of inputs—“intrinsic” inputs from genes, and “extrinsic” inputs from cell-cell interactions. Jokingly, Brenner called it the “British model” versus the “American model.” The British way, Brenner wrote, “is for cells to do their own thing and not to talk to their neighbors very much. Ancestry is what counts, and once a cell is born in a certain place it will stay there and develop according to rigid rules. The American way is quite the opposite. Ancestry does not count. . . . What counts is the interactions with its neighbors. It frequently exchanges information with its fellow cells and often has to move to accomplish its goals and find its proper place.” ([Location 3392](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=3392)) - Tags: [[blue]] - How can units of heredity generate the bewildering complexity of organisms? The answer lies in organization and interaction. A single master-regulatory gene might encode a protein with rather limited function: an on-and-off switch for twelve other target genes, say. But suppose the activity of the switch depends on the concentration of the protein, and the protein can be layered in a gradient across the body of an organism, with a high concentration at one end and a low concentration at the other. This protein might flick on all twelve of its targets in one part of an organism, eight in another segment, and only three in yet another. Each combination of target genes (twelve, eight, and three) might then intersect with yet other protein gradients, and activate and repress yet other genes. Add the dimensions of time and space to this recipe—i.e., when and where a gene might be activated or repressed—and you can begin to construct intricate fantasias of form. By mixing and matching hierarchies, gradients, switches, and circuits of genes and proteins, an organism can create the observed complexity of its anatomy and physiology. As one scientist described it, “. . . individual genes are not particularly clever—this one cares only about that molecule, that one only about some other molecule . . . But that simplicity is no barrier to building enormous complexity. If you can build an ant colony with just a few different kinds of simpleminded ants (workers, drones, and the like), think about what you can do with 30,000 cascading genes, deployed at will.” ([Location 3407](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=3407)) - Tags: [[blue]] - Genes operate in the same manner. Individual genes specify individual functions, but the relationship among genes allows physiology. The genome is inert without these relationships. That humans and worms have about the same number of genes—around twenty thousand—and yet the fact that only one of these two organisms is capable of painting the ceiling of the Sistine Chapel suggests that the number of genes is largely unimportant to the physiological complexity of the organism. “It is not what you have,” as a certain Brazilian samba instructor once told me, “it is what you do with it.” ([Location 3425](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=3425)) - Tags: [[blue]] - Perhaps the most useful metaphor to explain the relationship between genes, forms, and functions is one proposed by the evolutionary biologist and writer Richard Dawkins. Some genes, Dawkins suggests, behave like actual blueprints. A blueprint, Dawkins continues, is an exact architectural or mechanical plan, with a one-to-one correspondence between every feature of that plan and the structure that it encodes. A door is scaled down precisely twenty times, or a mechanical screw is placed precisely seven inches from the axle. “Blueprint” genes, by that same logic, encode the instructions to “build” one structure (or protein). The factor VIII gene makes only one protein, which serves mainly one function: it enables blood to form clots. Mutations in factor VIII are akin to mistakes in a blueprint. Their effect, like a missing doorknob or forgotten widget, is perfectly predictable. The mutated factor VIII gene fails to enable normal blood clotting, and the resulting disorder—bleeding without provocation—is the direct consequence of the function of the protein. The vast majority of genes, however, do not behave like blueprints. They do not specify the building of a single structure or part. Instead, they collaborate with cascades of other genes to enable a complex physiological function. These genes, Dawkins argues, are not like blueprints, but like recipes. In a recipe for a cake, for instance, it makes no sense to think that the sugar specifies the “top,” and the flour specifies the “bottom”; there is usually no one-to-one correspondence between an individual component of a recipe and one structure. A recipe provides instructions about process. ([Location 3430](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=3430)) - Tags: [[blue]] - such technologies were invented, their implications would be immense: the recipe of human instruction might be rewritten. Genetic mutations are selected over millennia, one scientist observed at the meeting, but cultural mutations can be introduced and selected in just a few years. The capacity to introduce “designed genetic changes” in humans might bring genetic change to the speed of cultural change. Some human diseases might be eliminated, the histories of individuals and families changed forever; the technology would reshape our notions of heredity, identity, illness, and future. As Gordon Tomkins, the biologist from UCSF, noted: “So for the first time, large numbers of people are beginning to ask themselves: What are we doing?” ([Location 3454](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=3454)) - Tags: [[blue]] - Unlike many viruses, Berg learned, SV40 could coexist quite peaceably with certain kinds of infected cells. Rather than producing millions of new virions after infection—and often killing the host cell as a result, as other viruses do—SV40 could insert its DNA into the host cell’s chromosome, and then lapse into a reproductive lull, until activated by specific cues. The compactness of the SV40 genome, and the efficiency with which it could be delivered into cells, made it an ideal vehicle to carry genes into human cells. Berg was gripped by the idea: if he could equip SV40 with a decoy “foreign” gene (foreign to the virus, at least), the viral genome would smuggle that gene into a human cell, thereby altering a cell’s hereditary information—a feat that would open novel frontiers for genetics. ([Location 3525](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=3525)) - Tags: [[blue]] - the real secret, as Berg and Lobban had independently figured out, was to forget that SV40 was a virus at all, and treat its genome as if it were a chemical. Genes may have been “inaccessible” in 1971—but DNA was perfectly accessible. Avery, after all, had boiled it in solution as a naked chemical, and it had still transmitted information between bacteria. Kornberg had added enzymes to it and made it replicate in a test tube. To insert a gene into the SV40 genome, all that Berg needed was a series of reactions. He needed an enzyme to cut open the genome circle, and an enzyme to “paste” a piece of foreign DNA into the SV40 genome necklace. Perhaps the virus—or, rather, the information contained in the virus—would then spring to life again. ([Location 3545](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=3545)) - Tags: [[blue]] - Berg called the hybrids “recombinant DNA”. It was a cannily chosen phrase, harkening back to the natural phenomenon of “recombination,” the genesis of hybrid genes during sexual reproduction. In nature, genetic information is frequently mixed and matched between chromosomes to generate diversity: DNA from the paternal chromosome swaps places with DNA from the maternal chromosome to generate “father:mother” gene hybrids—“crossing over,” as Morgan had called the phenomenon. Berg’s genetic hybrids, produced with the very tools that allowed genes to be cut, pasted, and repaired in their natural state in organisms, extended this principle beyond reproduction. Berg was also synthesizing gene hybrids, albeit with genetic material from different organisms, mixed and matched in test tubes. Recombination without reproduction: he was crossing over to a new cosmos of biology. ([Location 3589](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=3589)) - Tags: [[blue]] - Rather than viruses carrying bacterial genes, what might happen if Mertz created bacteria carrying viral genes? The inversion of logic—or rather, the inversion of organisms—carried a crucial technical advantage. Like many bacteria, E. coli carry minuscule extra chromosomes, called mini-chromosomes or plasmids. As with the SV40 genome, plasmids also exist as circular necklaces of DNA, and they live and replicate within the bacteria. As bacterial cells divide and grow, the plasmids are also replicated. If Mertz could insert SV40 genes into an E. coli plasmid, she realized, she could use the bacteria as a “factory” for the new gene hybrids. As the bacteria grew and divided, the plasmid—and the foreign gene inside it—would be amplified manyfold. Copy upon copy of the modified chromosome, and its payload of foreign genes, would be created by the bacteria. There would ultimately be millions of exact replicas of a piece of DNA—“clones.” ([Location 3603](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=3603)) - Tags: [[blue]] - Ironically, the very features that enable a cell to read DNA are the features that make it incomprehensible to humans—to chemists, in particular. DNA, as Schrödinger had predicted, was a chemical built to defy chemists, a molecule of exquisite contradictions—monotonous and yet infinitely varied, repetitive to the extreme and yet idiosyncratic to the extreme. Chemists generally piece together the structure of a molecule by breaking the molecule down into smaller and smaller parts, like puzzle pieces, and then assembling the structure from the constituents. But DNA, broken into pieces, degenerates into a garble of four bases—A, C, G, and T. You cannot read a book by dissolving all its words into alphabets. With DNA, as with words, the sequence carries the meaning. Dissolve DNA into its constituent bases, and it turns into a primordial four-letter alphabet soup. ([Location 3725](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=3725)) - Tags: [[blue]] - Sanger brought a chemist’s methodological rigor to the problem: the solution—as any chemist knew—was always in dissolution. Every protein is made of a sequence of amino acids strung into a chain—Methionine-Histidine-Arginine-Lysine or Glycine-Histidine-Arginine-Lysine, and so forth. To identify the sequence of a protein, Sanger realized, he would have to run a sequence of degradation reactions. He would snap off one amino acid from the end of the chain, dissolve it in solvents, and characterize it chemically—Methionine. And he would repeat the process, snapping off the next amino acid: Histidine. The degradation and identification would be repeated again and again—Arginine . . . snap . . . Lysine . . . snap—until he reached the end of the protein. It was like unstringing a necklace, bead by bead—reversing the cycle used by a cell to build a protein. Piece by piece, the disintegration of insulin would reveal the structure of its chain. In 1958, Sanger won the Nobel Prize for this landmark discovery. ([Location 3739](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=3739)) - Tags: [[blue]] - Inspiration came to Sanger unexpectedly in the winter of 1971—in the form of an inversion. He had spent decades learning to break molecules apart to solve their sequence. But what if he turned his own strategy upside down and tried to build DNA, rather than break it down? To solve a gene sequence, Sanger reasoned, one must think like a gene. Cells build genes all the time: each time a cell divides, it makes a copy of every gene. If a biochemist could strap himself to the gene-copying enzyme (DNA polymerase), straddling its back as it made a copy of DNA and keeping tabs as the enzyme added base upon base—A, C, T, G, C, C, C, and so forth—the sequence of a gene would become known. It was like eavesdropping on a copying machine: you could reconstruct the original from the copy. Once again, the mirror image would illuminate the original—Dorian Gray would be re-created, piece upon piece, from his reflection. ([Location 3758](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=3758)) - Tags: [[blue]] - In 1977, two scientists working independently, Richard Roberts and Phillip Sharp, discovered that most animal proteins were not encoded in long, continuous stretches of DNA, but were actually split into modules. In bacteria, every gene is a continuous, uninterrupted stretch of DNA, starting with the first triplet code (ATG) and running contiguously to the final “stop” signal. Bacterial genes do not contain separate modules, and they are not split internally by spacers. But in animals, and in animal viruses, Roberts and Sharp found that a gene was typically split into parts and interrupted by long stretches of stuffer DNA. ([Location 3777](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=3777)) - Tags: [[blue]] - At first, this split structure of genes seemed puzzling: Why would an animal genome waste such long stretches of DNA splitting genes into bits and pieces, only to stitch them back into a continuous message? But the inner logic of split genes soon became evident: by splitting genes into modules, a cell could generate bewildering combinations of messages out of a single gene. The word s . . . tru . . . c . . . t . . . ur . . . e can be spliced to yield cure and true and so forth, thereby creating vast numbers of variant messages—called isoforms—out of a single gene. From g . . . e . . . n . . . om . . . e you can use splicing to generate gene, gnome, and om. And modular genes also had an evolutionary advantage: the individual modules from different genes could be mixed and matched to build entirely new kinds of genes (c . . . om . . . e . . . t). Wally Gilbert, the Harvard geneticist, created a new word for these modules; he called them exons. The in-between stuffer fragments were termed introns. ([Location 3789](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=3789)) - Tags: [[blue]] - Introns are not the exception in human genes; they are the rule. Human introns are often enormous—spanning several hundreds of thousands of bases of DNA. And genes themselves are separated from each other by long stretches of intervening DNA, called intergenic DNA. Intergenic DNA and introns—spacers between genes and stuffers within genes—are thought to have sequences that allow genes to be regulated in context. To return to our analogy, these regions might be described as long ellipses scattered with occasional punctuation marks. The human genome can thus be visualized as: This . . . . . . is . . . . . . . . . . . . the . . . . . . (. . .) . . . s . . . truc . . . ture . . . . . . of . . . . . . your . . . . . . gen . . . om . . . e; The words represent genes. The long ellipses between the words represent the stretches of intergenic DNA. The shorter ellipses within the words (gen . . . ome . . . e) are introns. The parentheses and semicolons—punctuation marks—are regions of DNA that regulate genes. ([Location 3797](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=3797)) - Tags: [[blue]] - Say an immunologist was trying to solve a fundamental riddle in immunology: the mechanism by which T cells recognize and kill foreign cells in the body. For decades, it had been known that T cells sense the presence of invading cells and virus-infected cells by virtue of a sensor found on the surface of the T cell. The sensor, called the T cell receptor, is a protein made uniquely by T cells. The receptor recognizes proteins on the surface of foreign cells and binds to them. The binding, in turn, triggers a signal to kill the invading cell, and thereby acts as a defense mechanism for an organism. But what was the nature of the T cell receptor? Biochemists had approached the problem with their typical penchant for reduction: they had obtained vats upon vats of T cells, used soaps and detergents to dissolve the cell’s components into a gray, cellular froth, then distilled the membranes and lipids away, and purified and repurified the material into smaller and smaller parts to hunt down the culprit protein. Yet the receptor protein, dissolved somewhere in that infernal soup, had remained elusive. A gene cloner might take an alternative approach. Assume, for a moment, that the distinctive feature of the T cell receptor protein is that it is synthesized only in T cells, not in neurons, or ovaries, or liver cells. The gene for the receptor must exist in every human cell—human neurons, liver cells, and T cells have identical genomes, after all—but the RNA is made only in T cells. Could one compare the “RNA catalog” of two different cells, and thereby clone a functionally relevant gene from that catalog? The biochemist’s approach pivots on concentration: find the protein by looking where it’s most likely to be concentrated, and distill it out of the mix. The geneticist’s approach, in contrast, pivots on information: find the gene by searching for differences in “databases” created by two closely related cells and multiply the gene in bacteria via cloning. The biochemist distills forms; the gene cloner amplifies information. ([Location 3845](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=3845)) - Tags: [[blue]] - It is the impulse of science to try to understand nature, and the impulse of technology to try to manipulate it. Recombinant DNA had pushed genetics from the realm of science into the realm of technology. Genes were not abstractions anymore. They could be liberated from the genomes of organisms where they had been trapped for millennia, shuttled between species, amplified, purified, extended, shortened, altered, remixed, mutated, mixed, matched, cut, pasted, edited; they were infinitely malleable to human intervention. Genes were no longer just the subjects of study, but the instruments of study. There is an illuminated moment in the development of a child when she grasps the recursiveness of language: just as thoughts can be used to generate words, she realizes, words can be used to generate thoughts. Recombinant DNA had made the language of genetics recursive. Biologists had spent decades trying to interrogate the nature of the gene—but now it was the gene that could be used to interrogate biology. We had graduated, in short, from thinking about genes, to thinking in genes. ([Location 4058](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=4058)) - Tags: [[blue]] - Boyer’s plan for the synthesis of insulin was almost comically simple. He did not have the gene for human insulin at hand—no one did—but he would build it from scratch using DNA chemistry, nucleotide by nucleotide, triplet upon triplet—ATG, CCC, TCC, and so forth, all the way from the first triplet code to the last. He would make one gene for the A chain, and another gene for the B chain. He would insert both the genes in bacteria and trick them into synthesizing the human proteins. He would purify the two protein chains and then stitch them chemically to obtain the U-shaped molecule. It was a child’s plan. He would build the most ardently sought molecule in clinical medicine block by block, out of an Erector Set of DNA. ([Location 4146](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=4146)) - Tags: [[blue]] - Genentech’s approach to this problem was both ingenious and counterintuitive. Rather than patenting insulin as “matter” or “manufacture,” it concentrated its efforts, boldly, on a variation of “method.” Its application claimed a patent for a “DNA vehicle” to carry a gene into a bacterial cell, and thereby produce a recombinant protein in a microorganism. The claim was so novel—no one had ever produced a recombinant human protein in a cell for medicinal use—that the audacity paid off. On October 26, 1982, the US Patent and Trademark Office (USPTO) issued a patent to Genentech to use recombinant DNA to produce a protein such as insulin or somatostatin in a microbial organism. As one observer wrote: “effectively, the patent claimed, as an invention, [all] genetically modified microorganisms.” The Genentech patent would soon become one of the most lucrative, and most hotly disputed, patents in the history of technology. ([Location 4228](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=4228)) - Tags: [[blue]] - It is tempting to write the history of technology through products: the wheel; the microscope; the airplane; the Internet. But it is more illuminating to write the history of technology through transitions: linear motion to circular motion; visual space to subvisual space; motion on land to motion in air; physical connectivity to virtual connectivity. The production of proteins from recombinant DNA represented one such crucial transition in the history of medical technology. ([Location 4306](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=4306)) - Tags: [[blue]] - Although there are seemingly thousands of drugs in human usage—aspirin alone comes in dozens of variants—the number of molecular reactions targeted by these drugs is a minuscule fraction of the total number of reactions. Of the several million variants of biological molecules in the human body (enzymes, receptors, hormones—and so forth), only about 250—0.025 percent—are therapeutically modulated by our current pharmacopeia. If human physiology is visualized as a vast global telephone network with interacting nodes and networks, then our current medicinal chemistry touches only a fraction of a fraction of its complexity; medicinal chemistry is a pole operator in Wichita tinkering with a few lines in the network’s corner. The paucity of medicines has one principal reason: specificity. Nearly every drug works by binding to its target and enabling or disabling it—turning molecular switches on or off. To be useful, a drug must bind to its switches—but to only a selected set of switches; an indiscriminate drug is no different from a poison. Most molecules can barely achieve this level of discrimination—but proteins have been designed explicitly for this purpose. Proteins, recall, are the hubs of the biological world. They are the enablers and the disablers, the machinators, the regulators, the gatekeepers, the operators, of cellular reactions. They are the switches that most drugs seek to turn on and off. Proteins are thus poised to be some of the most potent and most discriminating medicines in the pharmacological world. But to make a protein, one needs its gene—and here recombinant DNA technology provided the crucial missing stepping-stone. The cloning of human genes allowed scientists to manufacture proteins—and the synthesis of proteins opened the possibility of targeting the millions of biochemical reactions in the human body. Proteins made it possible for chemists to intervene on previously impenetrable aspects of our physiology. The use of recombinant DNA to produce proteins thus marked a transition not just between one gene and one medicine, but between genes and a novel universe of drugs. ([Location 4312](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=4312)) - Tags: [[blue]] - It is, in short, quite likely to be a genetic disease—although not “genetic” in the same sense as sickle-cell anemia or hemophilia. No single gene governs the susceptibility to this bizarre illness. Multiple genes, spread across multiple chromosomes, specify the formation of the aqueducts of the brain during development—just as multiple genes, spread across multiple chromosomes, specify the formation of the wing in a fruit fly. Some of these genes, I learned, govern the anatomical configurations of the ducts and vessels of the ventricles (as an analogue, consider how “pattern-formation” genes can specify organs and structures in flies). Others encode the molecular channels that transmit fluids between the compartments. Yet other genes encode proteins that regulate the absorption of fluids from the brain into the blood, or vice versa. And since the brain and its ducts grow in the fixed cavity of the skull, genes that determine the size and shape of the skull also indirectly affect the proportions of the channels and the ducts. Variations in any of these genes may alter the physiology of the aqueducts and ventricles, changing the manner in which fluid moves through the channels. Environmental influences, such as aging or cerebral trauma, interpose further layers of complexity. There is no one-to-one mapping of one gene and one illness. Even if you inherit the entire set of genes that causes NPH in one person, you may still need an accident or an environmental trigger to “release” it (in my father’s case, the trigger was most likely his age). If you inherit a particular combination of genes—say, those that specify a particular rate of fluid absorption with those that specify a particular size of the aqueducts—you might have an increased risk of succumbing to the illness. It is a Delphic boat of a disease—determined not by one gene, but by the relationship between genes, and between genes and the environment. ([Location 4401](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=4401)) - Tags: [[blue]] - The challenge of genetics, as it moved from simple organisms to the human organism, was to confront new ways to think about the nature of heredity, information flow, function, and fate. How do genes intersect with environments to cause normalcy versus disease? For that matter, what is normalcy versus disease? How do the variations in genes cause variations in human form and function? How do multiple genes influence a single outcome? How can there be so much uniformity among humans, yet such diversity? How can the variants in genes sustain a common physiology, yet also produce unique pathologies? ([Location 4423](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=4423)) - Tags: [[blue]] - The final category of genetic diseases that McKusick characterized was the most complex—polygenic illnesses caused by multiple genes scattered diffusely throughout the genome. Unlike the first two categories, populated by rare and strange syndromes, these were familiar, pervasive, highly prevalent chronic illnesses—diabetes, coronary artery disease, hypertension, schizophrenia, depression, infertility, obesity. These illnesses lay on the opposite end of the One Gene–One Disease paradigm; they were Many Genes–Many Diseases. Hypertension, for instance, came in thousands of varieties and was under the influence of hundreds of genes, each exerting a minor additive effect on blood pressure and vascular integrity. Unlike Marfan or Down syndrome, where a single potent mutation or a chromosomal aberration was necessary and sufficient to cause the disease, the effect of any individual gene in polygenic syndromes was dulled. The dependence on environmental variables—diet, age, smoking, nutrition, prenatal exposures—was stronger. The phenotypes were variable and continuous, and the patterns of inheritance complex. The genetic component of the disease only acted as one trigger in a many-triggered gun—necessary, but not sufficient to cause the illness. ([Location 4490](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=4490)) - Tags: [[blue]] - multiple genes could influence a single aspect of physiology. Blood pressure, for instance, is regulated through a variety of genetic circuits, and abnormalities in one or many of these circuits all result in the same disease—hypertension. It is perfectly accurate to say “hypertension is a genetic disease,” but to also add, “There is no gene for hypertension.” Many genes tug and push the pressure of blood in the body, like a tangle of strings controlling a puppet’s arms. If you change the length of any of these individual strings, you change the configuration of the puppet. ([Location 4506](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=4506)) - Tags: [[blue]] - But how might sperm (or eggs, for that matter) be selected to carry specific enhanced genotypes? Could new genetic material be introduced into the human genome? Although the precise contours of the technology that would enable positive eugenics were yet unknown, several scientists considered this a mere technological hurdle that would be solved in the near future. The geneticist Hermann Muller, evolutionary biologists Ernst Mayr and Julian Huxley, and the population biologist James Crow were among the vociferous proponents of positive eugenics. Until the birth of eugenics, the only mechanism to select for beneficial human genotypes had been natural selection—governed by the brutal logic of Malthus and Darwin: the struggle for survival and the slow, tedious emergence of survivors. Natural selection, Crow wrote, was “cruel, blundering and inefficient.” In contrast, artificial genetic selection and manipulation could be based on “health, intelligence or happiness.” Support from scientists, intellectuals, writers, and philosophers poured into the movement. Francis Crick staunchly backed neo-eugenics, as did James Watson. James Shannon, director of the National Institutes of Health, told Congress that genetic screening was not just a “moral obligation of the medical profession, but a serious social responsibility as well.” ([Location 4695](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=4695)) - Tags: [[blue]] - In the history of science and technology too, breakthroughs seem to come in two fundamental forms. There are scale shifts—where the crucial advance emerges as a result of an alteration of size or scale alone (the moon rocket, as one engineer famously pointed out, was just a massive jet plane pointed vertically at the moon). And there are conceptual shifts—in which the advance arises because of the emergence of a radical new concept or idea. In truth, the two modes are not mutually exclusive, but reinforcing. Scale shifts enable conceptual shifts, and new concepts, in turn, demand new scales. The microscope opened a door to a subvisual world. Cells and intracellular organelles were revealed, raising questions about the inner anatomy and physiology of a cell, and demanding yet more powerful microscopes to understand the structures and functions of these subcellular compartments. ([Location 5018](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=5018)) - The one-gene-at-a-time approach worked perfectly for “monogenetic” diseases, such as cystic fibrosis and Huntington’s disease. But most common human diseases do not arise from single-gene mutations. These are not genetic illnesses as much as genomic illnesses: multiple genes, spread diffusely throughout the human genome, determine the risk for the illness. These diseases cannot be understood through the action of a single gene. They can only be understood, diagnosed, or predicted by understanding the interrelationships between several independent genes. ([Location 5050](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=5050)) - Tags: [[blue]] - That cancer was the result of alterations of such endogenous genetic pathways—a “distorted version of our normal selves,” as Harold Varmus, the cancer biologist, put it—was ferociously disquieting: for decades, scientists had hoped that some pathogen, such as a virus or bacterium, would be implicated as the universal cause of cancer, and might potentially be eliminated via a vaccine or antimicrobial therapy. The intimacy of the relationship between cancer genes and normal genes threw open a central challenge of cancer biology: How might the mutant genes be restored to their off or on states, while allowing normal growth to proceed unperturbed? This was—and still remains—the defining goal, the perennial fantasy, and the deepest conundrum, of cancer therapy. ([Location 5065](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=5065)) - Tags: [[blue]] - Normal cells could acquire these cancer-causing mutations through four mechanisms. The mutations could be caused by environmental insults, such as tobacco smoke, ultraviolet light, or X-rays—agents that attack DNA and change its chemical structure. Mutations could arise from spontaneous errors during cell division (every time DNA is replicated in a cell, there’s a minor chance that the copying process generates an error—an A switched to a T, G, or C, say). Mutant cancer genes could be inherited from parents, thereby causing hereditary cancer syndromes such as retinoblastoma and breast cancer that coursed through families. Or the genes could be carried into the cells via viruses, the professional gene carriers and gene swappers of the microbial world. In all four cases, the result converged on the same pathological process: the inappropriate activation or inactivation of genetic pathways that controlled growth, causing the malignant, dysregulated cellular division that was characteristic of cancer. ([Location 5071](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=5071)) - Tags: [[blue]] - Vogelstein had already discovered that cancers arise from a step-by-step process involving the accumulation of dozens of mutations in a cell. Gene by gene, a cell slouches toward cancer—acquiring one, two, four, and then dozens of mutations that tip its physiology from controlled growth to dysregulated growth. ([Location 5085](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=5085)) - Tags: [[blue]] - If the sequencing of cancer genomes—not just individual cancer genes—was necessary to understand the physiology and diversity of cancers, then it was all the more evident that the sequence of the normal genome had to be completed first. The human genome forms the normal counterpart to the cancer genome. A genetic mutation can be described only in the context of a normal or “wild-type” counterpart. Without that template of normalcy, one had little hope that the fundamental biology of cancer could be solved. ([Location 5091](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=5091)) - Tags: [[blue]] - Suppose schizophrenia is caused by a single, dominant, highly penetrant mutation in one gene. If one identical twin inherits that mutant gene, then the other will invariably inherit that gene. Both will manifest the disease, and the concordance between the twins should approach 100 percent. Fraternal twins and siblings should, on average, inherit that gene about half the time, and the concordance between them should fall to 50 percent. In contrast, suppose schizophrenia is not one disease but a family of diseases. Imagine that the cognitive apparatus of the brain is a complex mechanical engine, composed of a central axle, a main gearbox, and dozens of smaller pistons and gaskets to regulate and fine-tune its activity. If the main axle breaks, and the gearbox snaps, then the entire “cognition engine” collapses. This is analogous to the severe variant of schizophrenia: a combination of a few highly penetrant mutations in genes that control neural communication and development might cause the axle and the gears to collapse, resulting in severe deficits of cognition. Since identical twins inherit identical genomes, both will invariably inherit mutations in the axle and the gearbox genes. And since the mutations are highly penetrant, the concordance between identical twins will still approach 100 percent. But now imagine that the cognition engine can also malfunction if several of the smaller gaskets, spark plugs, and pistons do not work. In this case, the engine does not fully collapse; it sputters and gasps, and its dysfunction is more situational: it worsens in the winter. This, by analogy, is the milder variant of schizophrenia. The malfunction is caused by a combination of mutations, each with low penetrance: these are gasket-and-piston and spark-plug genes, exerting more subtle control on the overall mechanism of cognition. Here too identical twins, possessing identical genomes, will inherit, say, all five variants of the genes together—but since the penetrance is incomplete, and the triggers more situational, the concordance between identical twins might fall to only 30 or 50 percent. Fraternal twins and siblings, in contrast, will share only a few of these gene variants. Mendel’s laws guarantee that all five variants will rarely be inherited in toto by two siblings. The concordance between fraternal twins and siblings will fall even more sharply—to 5 or 10 percent. This pattern of inheritance is more commonly observed in schizophrenia. That identical twins share only a 50 percent concordance—i.e., if one twin is affected, then the other twin is affected only 50 percent of the time—clearly demonstrates that some other triggers (environmental factors or chance events) are required to tip the predisposition over an edge. But when a child of a schizophrenic parent is adopted at birth by a nonschizophrenic family, the child still has a 15 to 20 percent risk of developing the illness—about twentyfold higher than the general population—demonstrating… ([Location 5111](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=5111)) - Tags: [[blue]] - The most important technical breakthrough, perhaps, came from Kary Mullis, a biochemist studying gene replication. To sequence genes, it is crucial to have enough starting material of DNA. A single bacterial cell can be grown into hundreds of millions of cells, thereby supplying abundant amounts of bacterial DNA for sequencing. But it is difficult to grow hundreds of millions of human cells. Mullis had discovered an ingenious shortcut. He made a copy of a human gene in a test tube using DNA polymerase, then used that copy to make copies of the copy, then copied the multiple copies for dozens of cycles. Each cycle of copying amplified the DNA, resulting in an exponential increase in the yield of a gene. The technique was eventually called the polymerase chain reaction, or PCR, and would become crucial for the Human Genome Project. ([Location 5170](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=5170)) - Tags: [[blue]] - Intergenic DNA and introns—spacers between genes and stuffers within genes—do not encode any protein information.I Some of these stretches contain information to regulate and coordinate the expression of genes in time and space; they encode on and off switches appended to genes. Other stretches encode no known function. The structure of the human genome can thus be likened to a sentence that reads— This . . . . . . is the . . . . . . str . . . uc . . . . . . ture . . . , , , . . . of . . . your . . . ( . . . gen . . . ome . . . ) . . . —where the words correspond to the genes, the ellipses correspond to the spacers and stuffers, and the occasional punctuation marks demarcate the regulatory sequences of genes. ([Location 5245](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=5245)) - Tags: [[blue]] - Venter’s strategy was an expansion of the gene-fragment approach he had used with the brain—except with an important twist. This time he would shatter the bacterial genome into a million pieces. He would then sequence hundreds of thousands of fragments at random, then use their overlapping segments to assemble them to solve the entire genome. To return to our sentence analogy, imagine trying to assemble a word using the following word fragments: stru, uctu, ucture, structu, and ucture. A computer can use the overlapping segments to assemble the full word: structure. ([Location 5289](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=5289)) - Tags: [[blue]] - In contrast to TIGR’s strategy, which was to shred the genome to pieces, sequence at random, and reassemble the data post hoc, the Genome Project had chosen a more orderly approach—assembling and organizing the genomic fragments into a physical map (“Who is next to whom?”), confirming the identity and the overlaps of the clones, and then sequencing the clones in order. ([Location 5311](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=5311)) - Tags: [[blue]] - Proponents of the public Genome Project also feared the false intoxication of a half-finished genome: if gene sequencers left 10 percent of the genome incomplete, the full sequence would never be completed. “The real challenge of the Human Genome Project wasn’t starting the sequence. It was finishing the sequence of the genome. . . . If you left holes in the genome, but gave yourself the impression of completion, then no one would have the patience to finish the full sequence. Scientists would clap, dust their hands, pat their backs and move on. The draft would always remain a draft,” Lander later said. ([Location 5321](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=5321)) - Tags: [[blue]] - The discovery of ten thousand new proteins, with more than ten thousand new functions, would have amply justified the novelty of the project—yet the most surprising feature of the worm genome was not protein-encoding genes, but the number of genes that made RNA messages, but no protein. These genes—called “noncoding” (because they do not encode proteins)—were scattered through the genome, but they clustered on certain chromosomes. There were hundreds of them, perhaps thousands. Some noncoding genes were of known function: the ribosome, the giant intracellular machine that makes proteins, contains specialized RNA molecules that assist in the manufacture of proteins. Other noncoding genes were eventually found to encode small RNAs—called micro-RNAs—which regulate genes with incredible specificity. But many of these genes were mysterious and ill defined. They were not dark matter, but shadow matter, of the genome—visible to geneticists, yet unknown in function or significance. ([Location 5362](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=5362)) - Tags: [[blue]] - A gene specifies a function in an organism, yes—but a single gene can specify more than a single function. A gene need not provide instructions to build a protein: it can be used to encode RNA alone, and no proteins. It need not be a contiguous piece of DNA: it can be split into parts. It has regulatory sequences appended to it, but these sequences need not be immediately adjacent to a gene. ([Location 5378](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=5378)) - Tags: [[blue]] - animals probably have a relatively similar repertoire of proteins that need to be ‘called forth’ at any particular time. . . .” The difference between a more complex organism and a simpler one, “between a human and a nematode worm, is not that humans have more of those fundamental pieces of apparatus, but that they can call them into action in more complicated sequences and in a more complicated range of spaces.” It was not the size of the ship, yet again, but the way the planks were configured. The fly genome was its own Delphic boat. ([Location 5417](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=5417)) - Tags: [[blue]] - “The rediscovery of Mendel’s laws of heredity in the opening weeks of the 20th century sparked a scientific quest to understand the nature and content of genetic information that has propelled biology for the last hundred years. The scientific progress made [since that time] falls naturally into four main phases, corresponding roughly to the four quarters of the century.” “The first established the cellular basis of heredity: the chromosomes. The second defined the molecular basis of heredity: the DNA double helix. The third unlocked the informational basis of heredity [i.e., the genetic code], with the discovery of the biological mechanism by which cells read the information contained in genes, and with the invention of the recombinant DNA technologies of cloning and sequencing by which scientists can do the same.” The sequence of the human genome, the project asserted, marked the starting point of the “fourth phase” of genetics. This was the era of “genomics”—the assessment of the entire genomes of organisms, including humans. There is an old conundrum in philosophy that asks if an intelligent machine can ever decipher its own instruction manual. For humans, the manual was now complete. Deciphering it, reading it, and understanding it would be quite another matter. ([Location 5490](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=5490)) - Tags: [[blue]] - It encodes about 20,687 genes in total—only 1,796 more than worms, 12,000 fewer than corn, and 25,000 fewer genes than rice or wheat. The difference between “human” and “breakfast cereal” is not a matter of gene numbers, but of the sophistication of gene networks. It is not what we have; it is how we use it. ([Location 5525](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=5525)) - Tags: [[blue]] - It is fiercely inventive. It squeezes complexity out of simplicity. It orchestrates the activation or repression of certain genes in only certain cells and at certain times, creating unique contexts and partners for each gene in time and space, and thus produces near-infinite functional variation out of its limited repertoire. And it mixes and matches gene modules—called exons—within single genes to extract even further combinatorial diversity out of its gene repertoire. These two strategies—gene regulation and gene splicing—appear to be used more extensively in the human genome than in the genomes of most organisms. More than the enormity of gene numbers, the diversity of gene types, or the originality of gene function, it is the ingenuity of our genome that is the secret to our complexity. ([Location 5527](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=5527)) - Tags: [[blue]] - It is dynamic. In some cells, it reshuffles its own sequence to make novel variants of itself. Cells of the immune system secrete “antibodies”—missilelike proteins designed to attach themselves to invading pathogens. But since pathogens are constantly evolving, antibodies must also be capable of changing; an evolving pathogen demands an evolving host. The genome accomplishes this counter-evolution by reshuffling its genetic elements—thereby achieving astounding diversity (s . . . tru . . . c . . . t . . . ure and g . . . en . . . ome can be reshuffled to form an entirely new word c . . . ome . . . t). The reshuffled genes generate the diversity of antibodies. In these cells, every genome is capable of giving rise to an entirely different genome. ([Location 5533](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=5533)) - Tags: [[blue]] - Genes, oddly, comprise only a minuscule fraction of it. An enormous proportion—a bewildering 98 percent—is not dedicated to genes per se, but to enormous stretches of DNA that are interspersed between genes (intergenic DNA) or within genes (introns). These long stretches encode no RNA, and no protein: they exist in the genome either because they regulate gene expression, or for reasons that we do not yet understand, or because of no reason whatsoever (i.e., they are “junk” DNA). If the genome were a line stretching across the Atlantic Ocean between North America and Europe, genes would be occasional specks of land strewn across long, dark tracts of water. Laid end to end, these specks would be no longer than the largest Galápagos island or a train line across the city of Tokyo. ([Location 5544](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=5544)) - Tags: [[blue]] - Throughout much of the history of human biology, as the science writer Matt Ridley noted, genes too were largely perceived in mirror writing—identified by the abnormality or disease caused when they mutated. Hence the cystic fibrosis gene, the Huntington’s gene, the breast-cancer-causing BRCA1 gene, and so forth. To a biologist the nomenclature is absurd: the function of the BRCA1 gene is not to cause breast cancer when mutated, but to repair DNA when normal. The sole function of the “benign” breast cancer gene BRCA1 is to make sure that DNA is repaired when it is damaged. ([Location 5594](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=5594)) - Tags: [[blue]] - The gene called wingless in fruit flies encodes a protein whose real function is not to make wingless insects, but to encode instructions to build wings. Naming a gene cystic fibrosis (or CF), as Ridley observed, is “as absurd as defining the organs of the body by the diseases they get: livers are there to cause cirrhosis, hearts to cause heart attacks, and brains to cause strokes.” ([Location 5602](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=5602)) - Tags: [[blue]] - Vigilant readers may have noted that the two sentences signaled the twin ambitions of a new science. Traditionally, human genetics had concerned itself largely with pathology—with “diseases responsible for much human suffering.” But armed with new tools and methods, genetics could also roam freely to explore aspects of human biology that had hitherto seemed impenetrable to it. Genetics had crossed over from the strand of pathology to the strand of normalcy. The new science would be used to understand history, language, memory, culture, sexuality, identity, and race. It would, in its most ambitious fantasies, try to become the science of normalcy: of health, of identity, of destiny. ([Location 5610](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=5610)) - Tags: [[blue]] - Wilson realized that this technique could be applied not just across a family, but across an entire population of organisms. Variations in genes could be used to create a map of relatedness. And genetic diversity could be used to measure the oldest populations within a species: a tribe that has the most genetic diversity within it is older than a tribe with little or no diversity. ([Location 5683](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=5683)) - Tags: [[blue]] - when Wilson measured the overall diversity of the human mitochondrial genome, he found it to be surprisingly small—less diverse than the corresponding genomes of chimpanzees. Modern humans, in other words, are substantially younger and substantially more homogenous than chimpanzees (every chimp might look like every other chimp to human eyes, but to a discerning chimpanzee, it is humans that are vastly more alike). ([Location 5704](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=5704)) - Tags: [[blue]] - “You get less and less variation the further you go from Africa,” Feldman wrote. “Such a pattern fits the theory that the first modern humans settled the world in stepping-stone fashion after leaving Africa less than 100,000 years ago. As each small group of people broke away to found a new region, it took only a sample of the parent population’s genetic diversity.” ([Location 5716](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=5716)) - Tags: [[blue]] - The oldest human populations—their genomes peppered with diverse and ancient variations—are the San tribes of South Africa, Namibia, and Botswana, and the Mbuti Pygmies, who live deep in the Ituri forest in the Congo. The “youngest” humans, in contrast, are the indigenous North Americans who left Europe, and crossed into the Seward peninsula in Alaska through the icy cleft of the Bering Strait, some fifteen to thirty thousand years ago. This theory of human origin and migration, corroborated by fossil specimens, geological data, tools from archaeological digs, and linguistic patterns, has overwhelmingly been accepted by most human geneticists. It is called the Out of Africa theory, or the Recent Out of Africa model (the recent reflecting the surprisingly modern evolution of modern humans, and its acronym, ROAM, a loving memento to an ancient peripatetic urge that seems to rise directly out of our genomes). ([Location 5718](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=5718)) - Tags: [[blue]] - The exclusively female origin of all the mitochondria in an embryo has an important consequence. All humans—male or female—must have inherited their mitochondria from their mothers, who inherited their mitochondria from their mothers, and so forth, in an unbroken line of female ancestry stretching indefinitely into the past. (A woman also carries the mitochondrial genomes of all her future descendants in her cells; ironically, if there is such a thing as a “homunculus,” then it is exclusively female in origin—technically, a “femunculus”?) Now imagine an ancient tribe of two hundred women, each of whom bears one child. If the child happens to be a daughter, the woman dutifully passes her mitochondria to the next generation, and, through her daughter’s daughter, to a third generation. But if she has only a son and no daughter, the woman’s mitochondrial lineage wanders into a genetic blind alley and becomes extinct (since sperm do not pass their mitochondria to the embryo, sons cannot pass their mitochondrial genomes to their children). Over the course of the tribe’s evolution, tens of thousands of such mitochondrial lineages will land on lineal dead ends by chance, and be snuffed out. And here is the crux: if the founding population of a species is small enough, and if enough time has passed, the number of surviving maternal lineages will keep shrinking, and shrinking further, until only a few are left. If half of the two hundred women in our tribe have sons, and only sons, then one hundred mitochondrial lineages will dash against the glass pane of male-only heredity and vanish in the next generation. Another half will dead-end into male children in the second generation, and so forth. By the end of several generations, all the descendants of the tribe, male or female, might track their mitochondrial ancestry to just a few women. For modern humans, that number has reached one: each of us can trace our mitochondrial lineage to a single human female who existed in Africa about two hundred thousand years ago. She is the common mother of our species. We do not know what she looked like, although her closest modern-day relatives are women of the San tribe from Botswana or Namibia. I find the idea of such a founding mother endlessly mesmerizing. In human genetics, she is known by a beautiful name—Mitochondrial Eve. ([Location 5733](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=5733)) - Tags: [[blue]] - Wallace Sayre, the political scientist, liked to quip that academic disputes are often the most vicious because the stakes are so overwhelmingly low. By similar logic, perhaps our increasingly shrill debates on race should begin with the recognition that the actual range of human genomic variation is strikingly low—lower than in many other species (lower, remember, than in chimpanzees). Given our rather brief tenure on earth as a species, we are much more alike than unlike each other. ([Location 5792](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=5792)) - Tags: [[blue]] - Note: This is a fallacious conclusion, and one the author jumps to probably because he wants it to be true. As he has already stated earlier, not all mutations have the same effect. Many have little to no distinctive effect in our specific environment, while in others the change of a single nucleotide base can be catastrophic. Thus, looking simple at the amount of variation doesn’t tell us the phenotype-level changes that occurred because of that variation. For example, intelligence and everything that comes with it (cultural output, education, law-following, etc) is likely the most important phenotype in our society today. If there is a group that experienced strong selective pressure for intelligence (eg. Ashkenazi Jews who were confined in Europe to work much more intellectually-demanding jobs since they could not own land), then we would perceive a large difference in phenotype between that group and one that NEVER had evolutionary pressure encouraging the phenotype that is successful in urban environments. Chimpanzee populations may have accumulated more random mutations and thus genetic diversity, but humans have a broader range of environments (eg city dwelling vs hunter gatherers, both exist today) and so the success of certain PHENOTYPES has a much broader range - Does knowing that someone is of African versus European descent, say, allow us to refine our understanding of their genetic traits, or their personal, physical, or intellectual attributes in a meaningful manner? Or is there so much variation within Africans and Europeans that intraracial diversity dominates the comparison, thereby making the category “African” or “European” moot? We now know precise and quantitative answers to these questions. A number of studies have tried to quantify the level of genetic diversity of the human genome. The most recent estimates suggest that the vast proportion of genetic diversity (85 to 90 percent) occurs within so-called races (i.e., within Asians or Africans) and only a minor proportion (7 percent) between racial groups (the geneticist Richard Lewontin had estimated a similar distribution as early as 1972). Some genes certainly vary sharply between racial or ethnic groups—sickle-cell anemia is an Afro-Caribbean and Indian disease, and Tay-Sachs disease has a much higher frequency in Ashkenazi Jews—but for the most part, the genetic diversity within any racial group dominates the diversity between racial groups—not marginally, but by an enormous amount. This degree of intraracial variability makes “race” a poor surrogate for nearly any feature: in a genetic sense, an African man from Nigeria is so “different” from another man from Namibia that it makes little sense to lump them into the same category. ([Location 5811](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=5811)) - Tags: [[blue]] - Note: Again, this is a fallacious conclusion. Raw amounts of variation can be mostly inconsequential. In contrast, it is possible that selective pressures on two different populations caused a strong divergence in one particular trait that exerts an enormous influence on phenotype, even if it is a small percentage of the full human genome - Is g heritable? In a certain sense, yes. In the 1950s, a series of reports suggested a strong genetic component. Of these, twin studies were the most definitive. When identical twins who had been reared together—i.e., with shared genes and shared environments—were tested in the early fifties, psychologists had found a striking degree of concordance in their IQs, with a correlation value of 0.86.III In the late eighties, when identical twins who were separated at birth and reared separately were tested, the correlation fell to 0.74—still a striking number. But the heritability of a trait, no matter how strong, may be the result of multiple genes, each exerting a relatively minor effect. If that was the case, identical twins would show strong correlations in g, but parents and children would be far less concordant. IQ followed this pattern. The correlation between parents and children living together, for instance, fell to 0.42. With parents and children living apart, the correlation collapsed to 0.22. Whatever the IQ test was measuring, it was a heritable factor, but one also influenced by many genes and possibly strongly modified by environment—part nature and part nurture. The most logical conclusion from these facts is that while some combination of genes and environments can strongly influence g, this combination will rarely be passed, intact, from parents to their children. Mendel’s laws virtually guarantee that the particular permutation of genes will scatter apart in every generation. And environmental interactions are so difficult to capture and predict that they cannot be reproduced over time. Intelligence, in short, is heritable (i.e., influenced by genes), but not easily inheritable (i.e., moved down intact from one generation to the next). ([Location 5889](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=5889)) - Tags: [[blue]] - social psychologist Claude Steele demonstrated that when black students are asked to take an IQ test under the pretext that they are being tested to try out a new electronic pen, or a new way of scoring, they perform well. Told that they are being tested for “intelligence,” however, their scores collapse. The real variable being measured, then, is not intelligence but an aptitude for test taking, or self-esteem, or simply ego or anxiety. ([Location 5931](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=5931)) - Tags: [[blue]] - But the final fatal flaw in The Bell Curve is something far simpler, a fact buried so inconspicuously in a single throwaway paragraph in an eight-hundred-page book that it virtually disappears. If you take African-Americans and whites with identical IQ scores, say 105, and measure their performance in various subtests for intelligence, black children often score better in certain sets (tests of short-term memory and recall, for instance), while whites often score better in others (tests of visuospatial and perceptual changes). In other words, the way an IQ test is configured profoundly affects the way different racial groups, and their gene variants, perform on it: alter the weights and balances within the same test, and you alter the measure of intelligence. ([Location 5936](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=5936)) - Tags: [[blue]] - When a gene variant reduces an organism’s fitness in a particular environment—a hairless man in Antarctica—we call the phenomenon genetic illness. When the same variant increases fitness in a different environment, we call the organism genetically enhanced. The synthesis of evolutionary biology and genetics reminds us that these judgments are meaningless: enhancement or illness are words that measure the fitness of a particular genotype to a particular environment; if you alter the environment, the words can even reverse their meanings. ([Location 5963](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=5963)) - Tags: [[blue]] - When Stevens used Boveri’s chromosome-staining method on male and female worms, the answer leaped out of the microscope: a variation in just one chromosome correlated perfectly with the worm’s sex. Mealworms have twenty chromosomes in all—ten pairs (most animals have paired chromosomes; humans have twenty-three pairs). Cells from female worms inevitably possessed ten matched pairs. Cells from male worms, in contrast, had two unpaired chromosomes—a small, nublike band and a larger chromosome. Stevens suggested that the presence of the small chromosome was sufficient to determine sex. She termed it the sex chromosome. ([Location 6103](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=6103)) - Tags: [[blue]] - Stevens’s work was corroborated by that of her close collaborator, the cell biologist Edmund Wilson, who simplified Stevens’s terminology, calling the male chromosome Y, and the female X. In chromosomal terms, male cells were XY, and females were XX. The egg contains a single X chromosome, Wilson reasoned. When a sperm carrying a Y chromosome fertilizes an egg, it results in an XY combination, and maleness is determined. When a sperm carrying an X chromosome meets a female egg, the result is XX, which determines femaleness. Sex was not determined by right or left testicles, but by a similarly random process—by the nature of the genetic payload of the first sperm to reach and fertilize an egg. ([Location 6110](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=6110)) - Tags: [[blue]] - In fact, such humans existed—although identifying them was a much more complicated task than anticipated. In 1955, Gerald Swyer, an English endocrinologist investigating female infertility, had discovered a rare syndrome that made humans biologically female but chromosomally male. “Women” born with “Swyer syndrome” were anatomically and physiologically female throughout childhood, but did not achieve female sexual maturity in early adulthood. When their cells were examined, geneticists discovered that these “women” had XY chromosomes in all their cells. Every cell was chromosomally male—yet the person built from these cells was anatomically, physiologically, and psychologically female. A “woman” with Swyer syndrome had been born with the male chromosomal pattern (i.e., XY chromosomes) in all of her cells, but had somehow failed to signal “maleness” to her body. The most likely scenario behind Swyer syndrome was that the master-regulatory gene that specifies maleness had been inactivated by a mutation, leading to femaleness. At MIT, a team led by the geneticist David Page had used such sex-reversed women to map the male-determinant gene to a relatively narrow region of the Y chromosome. ([Location 6142](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=6142)) - Tags: [[blue]] - The SRY gene indubitably controls sex determination in an on/off manner. Turn SRY on, and an animal becomes anatomically and physiologically male. Turn it off, and the animal becomes anatomically and physiologically female. But to enable more profound aspects of gender determination and gender identity, SRY must act on dozens of targets—turning them on and off, activating some genes and repressing others, like a relay race that moves a baton from hand to hand. These genes, in turn, integrate inputs from the self and the environment—from hormones, behaviors, exposures, social performance, cultural role-playing, and memory—to engender gender. What we call gender, then, is an elaborate genetic and developmental cascade, with SRY at the tip of the hierarchy, and modifiers, integrators, instigators, and interpreters below. This geno-developmental cascade specifies gender identity. To return to an earlier analogy, genes are single lines in a recipe that specifies gender. The SRY gene is the first line in the recipe: “Start with four cups of flour.” If you fail to start with the flour, you will certainly not bake anything close to a cake. But infinite variations fan out of that first line—from the crusty baguette of a French bakery to the eggy mooncakes of Chinatown. ([Location 6257](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=6257)) - Tags: [[blue]] - The punch line of the paper was presented in a single table—unusual for Science, where papers typically contain dozens of figures. Over nearly eleven years, the Minnesota group had subjected the twins to battery upon battery of detailed physiological and psychological tests. In test upon test, the similarities between twins remained striking and consistent. The correlations between physical features had been expected: the number of fingerprint ridges on the thumb, for instance, was virtually identical, with a correlational value of 0.96 (a value of 1 reflects complete concordance or absolute identity). IQ testing also revealed a strong correlation of about 0.70, corroborating previous studies. But even the most mysterious and profound aspects of personality, preferences, behaviors, attitudes, and temperament, tested broadly using multiple independent tests, showed strong correlations between 0.50 and 0.60—virtually identical to the correlation between identical twins that had been reared together. (As a sense of the strength of this association, consider that the correlation between height and weight in human populations lies between 0.60 and 0.70, and between educational status and income is about 0.50. The concordance among twins for type 1 diabetes, an illness considered unequivocally genetic, is only 0.35.) The most intriguing correlations obtained by the Minnesota study were also among the most unexpected. Social and political attitudes between twins reared apart were just as concordant as those between twins reared together: liberals clustered with liberals, and orthodoxy was twinned with orthodoxy. Religiosity and faith were also strikingly concordant: twins were either both faithful or both nonreligious. Traditionalism, or “willingness to yield to authority,” was significantly correlated. So were characteristics such as “assertiveness, drive for leadership, and a taste for attention.” Other studies on identical twins continued to deepen the effect of genes on human personality and behavior. Novelty seeking and impulsiveness were found to have striking degrees of correlation. Experiences that one might have imagined as intensely personal were, in fact, shared between twins. “Empathy, altruism, sense of equity, love, trust, music, economic behavior, and even politics are partially hardwired.” As one startled observer wrote, “A surprisingly high genetic component was found in the ability to be enthralled by an esthetic experience such as listening to a symphonic concert.” Separated by geographic and economic continents, when two brothers, estranged at birth, were brought to tears by the same Chopin nocturne at night, they seemed to be responding to some subtle, common chord struck by their genomes. ([Location 6531](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=6531)) - Tags: [[blue]] - It is a testament to the unsettling beauty of the genome that it can make the real world “stick.” Our genes do not keep spitting out stereotypical responses to idiosyncratic environments: if they did, we too would devolve into windup automatons. Hindu philosophers have long described the experience of “being” as a web—jaal. Genes form the threads of the web; the detritus that sticks is what transforms every individual web into a being. ([Location 6678](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=6678)) - Tags: [[blue]] - Identical twins have exactly the same genetic code as each other. They share the same womb, and usually they are brought up in very similar environments. When we consider this, it doesn’t seem surprising that if one of the twins develops schizophrenia, the chance that his or her twin will also develop the illness is very high. In fact, we have to start wondering why it isn’t higher. Why isn’t the figure 100 percent? —Nessa Carey, The Epigenetics Revolution ([Location 6704](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=6704)) - Tags: [[blue]] - The transfer of an adult frog nucleus (i.e., all its genes) into an empty egg worked: perfectly functional tadpoles were born, and each of these tadpoles carried a perfect replica of the genome of the adult frog. If Gurdon transferred the nuclei from multiple adult cells drawn from the same frog into multiple evacuated eggs, he could produce tadpoles that were perfect clones of each other, and clones of the original donor frog. The process could be repeated ad infinitum: clones made from clones from clones, all carrying exactly the same genotype—reproductions without reproduction. Gurdon’s experiment incited the imagination of biologists—not the least because it seemed like a science-fiction fantasy brought to life. In one experiment, he produced eighteen clones from the intestinal cells of a single frog. Placed into eighteen identical chambers, they were like eighteen doppelgängers, inhabiting eighteen parallel universes. The scientific principle at stake was also provocative: the genome of an adult cell, having reached its full maturity, had been bathed briefly in the elixir of an egg cell and then emerged fully rejuvenated as an embryo. The egg cell, in short, had everything necessary—all the regulatory factors needed to drive a genome backward through developmental time into a functional embryo. In time, variations on Gurdon’s method would be generalized to other animals. It would lead, famously, to the cloning of Dolly, the sheep, the only higher organism reproduced without reproduction ([Location 6810](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=6810)) - Tags: [[blue]] - But for all the remarkable features of Gurdon’s experiment, it was his lack of success that was just as revealing. Adult intestinal cells could certainly give rise to tadpoles, but despite Gurdon’s laborious technical ministrations, they did so with great reluctance: his success rate at turning adult cells into tadpoles was abysmal. This demanded an explanation beyond classical genetics. The DNA sequence in the genome of an adult frog, after all, is identical to the DNA sequence of an embryo or a tadpole. Is it not the fundamental principle of genetics that all cells contain the same genome, and it is the manner in which these genes are deployed in different cells, turned on and off based on cues, that controls the development of an embryo into an adult? But if genes are genes are genes, then why was the genome of an adult cell so inefficiently coaxed backward into an embryo? And why, as others discovered, were nuclei from younger animals more pliant to this age reversal than those from older animals? Again, as with the Hongerwinter study, something must have been progressively imprinted on the adult cell’s genome—some cumulative, indelible mark—that made it difficult for that genome to move back in developmental time. That mark could not live in the sequence of genes themselves, but had to be etched above them: it had to be epigenetic. Gurdon returned to Waddington’s question: What if every cell carries an imprint of its history and its identity in its genome—a form of cellular memory? ([Location 6823](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=6823)) - Tags: [[blue]] - What purpose does X inactivation serve? Since females have two X chromosomes, while males have only one, female cells inactivate one X chromosome to equalize the “dose” of genes from the two X chromosomes. This random inactivation of the X has an important biological consequence: the female body is a mosaic of two types of cells. For the most part, this random silencing of one X chromosome is invisible—unless one of the X chromosomes (from the father, say) happens to carry a gene variant that produces a visible trait. In that case, one cell might express that variant, while its neighboring cell would lack that function—producing a mosaic-like effect. In cats, for instance, one gene for coat color lives on the X chromosome. The random inactivation of the X chromosome causes one cell to have a color pigment, while its neighbor has a different color. Epigenetics, not genetics, solves the conundrum of a female tortoiseshell cat. ([Location 6846](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=6846)) - Tags: [[blue]] - In the late 1970s, scientists working on gene-silencing discovered that the attachment of a small molecule—a methyl group—to some parts of DNA was correlated with a gene’s turning off. One of the chief instigators of this process was later found to be an RNA molecule, called XIST. The RNA molecule “coats” parts of the X chromosome and is thought to be crucial to the silencing of that chromosome. These methyl tags decorated the strands of DNA, like charms on a necklace, and they were recognized as shutdown signals for certain genes. ([Location 6857](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=6857)) - Tags: [[blue]] - Histones hang tightly to DNA and wrap it into coils and loops, forming scaffolds for the chromosome. When scaffolding changes, the activity of a gene can change—akin to altering the properties of a material by changing the way that it is packaged (a skein of silk packed into a ball has very different properties from that same skein stretched into a rope). A “molecular memory” could potentially be stamped on a gene—this time, indirectly, by attaching the signal to proteins (there is enormous debate within the field of epigenetics whether some—or any—histone modifications carry consequential effects on the activity of a gene, or whether some of these histone changes are merely “bystanders” or side-effects of a gene’s activity). The heritability and stability of these histone marks, and the mechanism to ensure that the marks appear in the right genes at the right time, are still under investigation—but simple organisms, such as yeast and worms, can seemingly transmit these histone marks across several generations. ([Location 6865](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=6865)) - Tags: [[blue]] - This was the reason that Gurdon, despite all his experimental ministrations, had rarely been able to coax an adult intestinal cell backward in developmental time to become an embryonic cell and then a full-fledged frog: the genome of the intestinal cell had been tagged with too many epigenetic “notes” for it to be easily erased and transformed into the genome of an embryo. Like human memories that persist despite attempts to alter them, the chemical scribbles overwritten on the genome can be changed—but not easily. These notes are designed to persist so that a cell can lock its identity into place. Only embryonic cells have genomes that are pliant enough to acquire many different kinds of identities—and can thus generate all the cell types in the body. Once the cells of the embryo have taken up fixed identities—turned into intestinal cells or blood cells or nerve cells, say—there is rarely any going back (hence Gurdon’s difficulty in making a tadpole out of a frog’s intestinal cell). ([Location 6888](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=6888)) - Tags: [[blue]] - The interplay between gene regulators and epigenetics partially solves the riddle of a cell’s individuality—but perhaps it can also solve the more tenacious riddle of an individual’s individuality. “Why are twins different?” we had asked earlier. Well, because idiosyncratic events are recorded through idiosyncratic marks in their bodies. But “recorded” in what manner? Not in the actual sequence of genes: if you sequence the genomes of a pair of identical twins every decade for fifty years, you get the same sequence over and over again. But if you sequence the epigenomes of a pair of twins over the course of several decades, you find substantial differences: the pattern of methyl groups attached to the genomes of blood cells or neurons is virtually identical between the twins at the start of the experiment, begins to diverge slowly over the first decade, and becomes substantially different over fifty years.VII ([Location 6896](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=6896)) - Tags: [[blue]] - Like Gurdon, again, Yamanaka began his attempt to reverse a cell’s identity with a normal cell from an adult mouse—this one from a fully grown mouse’s skin. Gurdon’s experiment had proved that factors present in an egg—proteins and RNA—could erase the marks of an adult cell’s genome and thereby reverse the fate of a cell and produce a tadpole from a frog cell. Yamanaka wondered whether he could identify and isolate these factors from an egg cell, then use them as molecular “erasers” of cellular fate. After a decades-long hunt, Yamanaka narrowed the mysterious factors down to proteins encoded by just four genes. He then introduced the four genes into an adult mouse’s skin cell. To Yamanaka’s astonishment, and to the subsequent amazement of scientists around the world, the introduction of these four genes into a mature skin cell caused a small fraction of the cells to transform into something resembling an embryonic stem cell. This stem cell could give rise to skin, of course, but also to muscle, bones, blood, intestines, and nerve cells. In fact, it could give rise to all cell types found in an entire organism. When Yamanaka and his colleagues analyzed the progression (or rather regression) of the skin cell to the embryo-like cell, they uncovered a cascade of events. Circuits of genes were activated or repressed. The metabolism of the cell was reset. Then, epigenetic marks were erased and rewritten. The cell changed shape and size. Its wrinkles unmarked, its stiffening joints made supple, its youth restored, the cell could now climb up Waddington’s slope. Yamanaka had expunged a cell’s memory, reversed biological time. The story comes with a twist. One of the four genes used by Yamanaka to reverse cellular fate is called c-myc Myc, the rejuvenation factor, is no ordinary gene: it is one of the most forceful regulators of cell growth and metabolism known in biology. Activated abnormally, it can certainly coax an adult cell back into an embryo-like state, thereby enabling Yamanaka’s cell-fate reversal experiment (this function requires the collaboration of the three other genes found by Yamanaka). But myc is also one of the most potent cancer-causing genes known in biology; it is also activated in leukemias and lymphomas, and in pancreatic, gastric, and uterine cancer. As in some ancient moral fable, the quest for eternal youthfulness appears to come at a terrifying collateral cost. The very genes that enable a cell to peel away mortality and age can also tip its fate toward malignant immortality, perpetual growth, and agelessness—the hallmarks of cancer. ([Location 6925](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=6925)) - Tags: [[blue]] - And when a human geneticist says, “Genetics cannot be used to manipulate complex states and behaviors because these are usually controlled by dozens of genes,” that geneticist is underestimating the capacity of one gene, such as a master regulator of genes, to “reset” entire states of being. If the activation of four genes can turn a skin cell into a pluripotent stem cell, if one drug can reverse the identity of a brain, and if a mutation in a single gene can switch sex and gender identity, then our genomes, and our selves, are much more pliable than we had imagined. ([Location 7002](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=7002)) - Tags: [[blue]] - The discontinuous nature of information would have carried an added benefit: a mutation could affect one gene, and only one gene, leaving the other genes unaffected. Mutations could now act on discrete modules of information rather than disrupting the function of the organism as a whole—thereby accelerating evolution. But that benefit came with a concomitant liability: too much mutation, and the information would be damaged or lost. What was needed, perhaps, was a backup copy—a mirror image to protect the original or to restore the prototype if damaged. Perhaps this was the ultimate impetus to create a double-stranded nucleic acid. The data in one strand would be perfectly reflected in the other and could be used to restore anything damaged; the yin would protect the yang. Life thus invented its own hard drive. ([Location 7070](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=7070)) - Tags: [[blue]] - Most stem cells reside in particular organs and tissues and give rise to a limited repertoire of cells. Stem cells in the bone marrow, for instance, only produce blood cells. There are stem cells in the crypts of the intestine that are dedicated to the production of intestinal cells. But embryonic stem cells, or ES cells, which arise from the inner sheath of an animal’s embryo, are vastly more potent; they can give rise to every cell type in the organism—blood, brains, intestines, muscles, bone, skin. Biologists use the word pluripotent to describe this property of ES cells. ([Location 7170](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=7170)) - Tags: [[blue]] - the real power of an ES cell lies, yet again, in a transition: like DNA, like genes, and like viruses, it is the intrinsic duality of its existence that makes this cell such a potent biological tool. Embryonic stem cells behave like other experimentally amenable cells in tissue culture. They can be grown in petri dishes; they can be frozen in vials and thawed back to life. The cells can be propagated in liquid broth for generations, and genes can be inserted into their genomes or excised from their genomes with relative ease. Yet, put the same cell into the right environment in the right context, and life literally leaps out of it. Mixed with cells from an early embryo and implanted into a mouse womb, the cells divide and form layers. They differentiate into all sorts of cells: blood, brain, muscle, liver—and even sperm and egg cells. These cells, in turn, organize themselves into organs and then become incorporated, miraculously, into a multilayered, multicellular organism—an actual mouse. Every experimental manipulation performed in the petri dish is thus carried forward into this mouse. The genetic modification of a cell in a dish “becomes” the genetic modification of an organism in a womb. It is a transition between lab and life. ([Location 7178](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=7178)) - Tags: [[blue]] - The anti-determinists want to say that DNA is a little side-show, but every disease that’s with us is caused by DNA. And [every disease] can be fixed by DNA. —George Church ([Location 7484](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=7484)) - Tags: [[blue]] - Familial schizophrenia (like normal human features such as intelligence and temperament) is thus highly heritable but only moderately inheritable. In other words, genes—hereditary determinants—are crucially important to the future development of the disorder. If you possess a particular combination of genes, the chance of developing the illness is extremely high: hence the striking concordance among identical twins. On the other hand, the inheritance of the disorder across generations is complex. Since genes are mixed and matched in every generation, the chance that you will inherit that exact permutation of variants from your father or mother is dramatically lower. In some families, perhaps, there are fewer gene variants, but with more potent effects—thereby explaining the recurrence of the disorder across generations. In other families, the genes may have weaker effects and require deeper modifiers and triggers—thereby explaining the infrequent inheritance. In yet other families, a single, highly penetrant gene is accidentally mutated in sperm or egg cells before conception, leading to the observed cases of sporadic schizophrenia.V ([Location 7635](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=7635)) - most genes, as Richard Dawkins describes them, are not “blueprints” but “recipes.” They do not specify parts, but processes; they are formulas for forms. If you change a blueprint, the final product is changed in a perfectly predictable manner: eliminate a widget specified in the plan, and you get a machine with a missing widget. But the alteration of a recipe or formula does not change the product in a predictable manner: if you quadruple the amount of butter in a cake, the eventual effect is more complicated than just a quadruply buttered cake (try it; the whole thing collapses in an oily mess). By similar logic, you cannot examine most gene variants in isolation and decipher their influence on form and fate. That a mutation in the gene MECP2, whose normal function is to recognize chemical modifications to DNA, may cause a form of autism is far from self-evident (unless you understand how genes control the neurodevelopmental processes that make a brain). ([Location 7782](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=7782)) - If the history of the last century taught us the dangers of empowering governments to determine genetic “fitness” (i.e., which person fits within the triangle, and who lives outside it), then the question that confronts our current era is what happens when this power devolves to the individual. It is a question that requires us to balance the desires of the individual—to carve out a life of happiness and achievement, without undue suffering—with the desires of a society that, in the short term, may be interested only in driving down the burden of disease and the expense of disability. And operating silently in the background is a third set of actors: our genes themselves, which reproduce and create new variants oblivious of our desires and compulsions—but, either directly or indirectly, acutely or obliquely, influence our desires and compulsions. Speaking at the Sorbonne in 1975, the cultural historian Michel Foucault once proposed that “a technology of abnormal individuals appears precisely when a regular network of knowledge and power has been established.” Foucault was thinking about a “regular network” of humans. But it could just as easily be a network of genes. ([Location 7919](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=7919)) - Tags: [[blue]] - There is in biology at the moment a sense of barely contained expectations reminiscent of the physical sciences at the beginning of the 20th century. It is a feeling of advancing into the unknown and [a recognition] that where this advance will lead is both exciting and mysterious. . . . The analogy between 20th-century physics and 21st-century biology will continue, for both good and ill. —“Biology’s Big Bang,” 2007 ([Location 7965](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=7965)) - Tags: [[blue]] - Conceptually, gene therapy comes in two distinct flavors. The first involves modifying the genome of a nonreproductive cell—say a blood, brain, or muscle cell. The genetic modification of these cells affects their function, but it does not alter the human genome for more than one generation. If a genetic change is introduced into a muscle or blood cell, the change is not transmitted into a human embryo; the altered gene is lost when the cell dies. Ashi DeSilva, Jesse Gelsinger, and Cynthia Cutshall are all examples of humans treated with non-germ-line gene therapy: in all three cases, blood cells—but not germ-line cells (i.e., sperm and egg)—were altered by the introduction of foreign genes. The second, more radical, form of gene therapy is to modify a human genome so that the change affects reproductive cells. Once a genomic change has been introduced into a sperm or egg—i.e., into the germ line of a human being—the change becomes self-propagating. The change is incorporated permanently into the human genome and transmitted from one generation to the next. The inserted gene becomes inextricably linked to the human genome. ([Location 7986](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=7986)) - Tags: [[blue]] - The protocol for this test was simple: ten men with a severe variant of the disease were injected with a single dose of a virus carrying a gene for factor IX. The presence of the virus-encoded protein was monitored in the blood for several months. Notably, this trial tested not just safety, but efficacy: the ten virus-injected patients were monitored for bleeding episodes, and for their use of additional factor IX by injection. Although the injection of the virus-borne gene increased the factor IX concentration to just 5 percent of the normal value, the effect on bleeding episodes was startling. The patients experienced a 90 percent reduction in bleeding incidents, and an equally dramatic reduction in their use of injected factor IX. The effect persisted over three years. The potent therapeutic effect of a mere 5 percent replacement of a missing protein is a beacon for the aspirations of gene therapists. It reminds us of the power of degeneracy in human biology: if only 5 percent of a clotting factor is sufficient to restore virtually all clotting function in human blood, then 95 percent of the protein must be superfluous—a buffer, or reservoir, possibly maintained in the human body as a backup in the event of a truly catastrophic bleed. If the same principle holds for other genetic diseases caused by single genes—for cystic fibrosis, say—then gene therapy might be vastly more tractable than had previously been imagined. Even the inefficient delivery of a therapeutic gene to a small subset of cells might be sufficient to treat an otherwise fatal disease. ([Location 8024](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=8024)) - Tags: [[blue]] - Charpentier told Doudna of her interest in bacterial immune systems—the mechanisms by which bacteria defend themselves against viruses. The war between viruses and bacteria has gone on for so long, and with such ferocity, that like ancient, conjoined enemies, each has become defined by the other: their mutual animosity has been imprinted in their genes. Viruses have evolved genetic mechanisms to invade and kill bacteria. And bacteria have counter-evolved genes to fight back. “A viral infection [is a] ticking time bomb,” Doudna knew. “A bacterium has only a few minutes to diffuse the bomb—before it gets destroyed itself.” ([Location 8094](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=8094)) - Tags: [[blue]] - Horvath and Barrangou, both employees of the Danish food company Danisco, were working on cheese-producing and yogurt-making bacteria. Some of these bacterial species, they found, had evolved a system to deliver coordinated slashes in the genomes of invading viruses to paralyze them. The system—a molecular switchblade of sorts—recognized serial-offender viruses by their DNA sequence. The cuts were not delivered at random places, but at specific sites in viral DNA. The bacterial defense system was soon found to involve at least two critical components. The first piece was the “seeker”—an RNA encoded in the bacterial genome that matched and recognized the DNA of the viruses. The principle for the recognition, yet again, was binding: the RNA “seeker” was able to find and recognize the DNA of an invading virus because it was a mirror image of that DNA—the yin to its yang. It was like carrying a permanent image of your enemy in your pocket—or, in the bacteria’s case, an inverted photograph, etched indelibly into its genome. The second element of the defense system was the “hitman.” Once the viral DNA had been recognized and matched as foreign (by its reverse-image), a bacterial protein named Cas9 was deployed to deliver the lethal gash to the viral gene. The “seeker” and the “hitman” worked in concert: the Cas9 protein delivered its cuts to the genome only after the sequence had been matched by the recognition element. It was a classic combination of collaborators—spotter and executor, drone and rocket, Bonnie and Clyde. ([Location 8099](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=8099)) - Tags: [[blue]] - In 2012, Doudna and Charpentier realized that the system was “programmable.” Bacteria, of course, only carry the images of viral genes so that they can seek and destroy viruses; they have no reason to recognize or cut other genomes. But Doudna and Charpentier learned enough about the self-defense system to trick it: by substituting a decoy recognition element, they could force the system to make intentional cuts in other genes and genomes. Switch the “seeker,” they found, and a different gene might be sought and cut. ([Location 8113](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=8113)) - Tags: [[blue]] - The system could be manipulated even further. When a gene is cut open, two ends of DNA are revealed, like severed string, and the ends are trimmed back. The cutting and trimming is meant to repair the broken gene—and the gene then tries to recover the lost information by seeking an intact copy. Matter has to conserve energy; the genome is designed to conserve information. Typically, a cut-open gene tries to recover the lost information from the other copy of the gene in the cell. But if a cell is flooded with foreign DNA, then the gene witlessly copies the information from this decoy DNA, rather than from its backup copy. The information written into the decoy DNA fragment is thus copied permanently into the genome—akin to erasing a word in a sentence and then forcibly writing a substitute in its place. A defined, predetermined genetic change can thus be written into a genome: the sequence ATGGGCCCG in a gene can be altered to ACCGCCGGG (or any desired sequence). A mutant cystic fibrosis gene can be corrected to the wild-type version; a gene to confer viral resistance can be introduced into an organism; the mutant BRCA1 gene can be reverted to wild type; the mutated Huntington’s gene, with its mirthless, singsong repeat, might be disrupted and deleted. The technique has been termed genome editing, or genomic surgery. ([Location 8123](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=8123)) - Tags: [[blue]] - An arcane microbial defense, devised by microbes, discovered by yogurt engineers, and reprogrammed by RNA biologists, has created a trapdoor to the transformative technology that geneticists had sought so longingly for decades: a method to achieve directed, efficient, and sequence-specific modification of the human genome. Richard Mulligan, the pioneer of gene therapy, had once fantasized about “clean, chaste gene therapy.” This system makes clean, chaste gene therapy feasible. ([Location 8137](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=8137)) - Tags: [[blue]] - But there’s a third strategy that may be the most approachable. Suppose a genetic change is introduced into human ES cells using standard gene-modification technologies. And now imagine that the gene-modified ES cells can be converted into reproductive cells—sperm and eggs. If ES cells are truly pluripotent stem cells, then they should be able to give rise to human sperm and eggs (a real human embryo, after all, generates its own germ cells—sperm or egg). Now consider a thought experiment: if a human embryo can be created by IVF using such gene-modified sperm or eggs, then the resultant embryo will necessarily carry these genetic changes in all its cells—including its sperm and egg cells. The preliminary steps of this process can be tested without changing or manipulating an actual human embryo—and can thus safely skirt the moral boundaries of human embryo manipulation.II Most critically, the process mimics the well-established protocols of IVF: a sperm and an egg are fertilized in vitro, and an early embryo is implanted into a woman’s body—a procedure that raises few qualms. It is a shortcut to germ-line gene therapy, a back door to transhumanism: the introduction of a gene into the human germ line is facilitated by the conversion of ES cells into germ cells. ([Location 8152](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=8152)) - Tags: [[blue]] - In the spring of 1939, Albert Einstein, mulling over recent advances in nuclear physics in his study at Princeton University, realized that every step required to achieve the creation of an unfathomably powerful weapon had been individually completed. The isolation of uranium, nuclear fission, the chain reaction, the buffering of the reaction, and its controlled release in a chamber had all fallen into place. All that was required was sequence: if you strung these reactions together in order, you obtained an atomic bomb. In 1972, at Stanford, Paul Berg stared at bands of DNA on a gel and found himself at a similar juncture. The cutting and pasting of genes, the creation of chimeras, and the introduction of these gene chimeras into bacterial and mammalian cells allowed scientists to engineer genetic hybrids between humans and viruses. All that was needed was the threading of these reactions into a sequence. We are at a similar moment—a quickening—for human genome engineering. Consider the following steps in sequence: (a) the derivation of a true human embryonic stem cell (capable of forming sperm and eggs); (b) a method to create reliable, intentional genetic modifications in that cell line; (c) the directed conversion of that gene-modified stem cell into human sperm and eggs; (d) the production of human embryos from these modified sperm and eggs by IVF . . . and you arrive, rather effortlessly, at genetically modified humans. There is no sleight of hand here; each of the steps lies within the reach of current technology. Of course, much remains unexplored: Can every gene be efficiently altered? What are the collateral effects of such alterations? Will the sperm and egg cells formed from ES cells truly generate functional human embryos? Many, many minor technical hurdles remain. But the pivotal pieces of the jigsaw puzzle have fallen into place. ([Location 8177](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=8177)) - Tags: [[blue]] - CRISPR/Cas9-based genomic engineering, in contrast, allows us to add information to the genome: a gene can be changed in an intentional manner, and new genetic code can be written into the human genome. “This reality means that germline manipulation would largely be justified by attempts to ‘improve ourselves,’ ” Francis Collins wrote to me. “That means that someone is empowered to decide what an ‘improvement’ is. Anyone contemplating such action should be aware of their hubris.” The crux, then, is not genetic emancipation (freedom from the bounds of hereditary illnesses), but genetic enhancement (freedom from the current boundaries of form and fate encoded by the human genome). The distinction between the two is the fragile pivot on which the future of genome editing whirls. If one man’s illness is another man’s normalcy, as this history teaches us, then one person’s understanding of enhancement may be another’s conception of emancipation (“why not make ourselves a little better?” as Watson asks). ([Location 8214](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=8214)) - Tags: [[blue]] - There is nothing about genes or genomes that makes them inherently resistant to chemical and biological manipulation. The standard notion that “most human features are the result of complex gene-environment interactions and most are the result of multiple genes” is absolutely true. But while these complexities constrain the ability to manipulate genes, they leave plenty of opportunity for potent forms of gene modification. Master regulators that affect dozens of genes are common in human biology. An epigenetic modifier may be designed to change the state of hundreds of genes with a single switch. The genome is replete with such nodes of intervention. ([Location 8305](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=8305)) - Tags: [[blue]] - History repeats itself, in part because the genome repeats itself. And the genome repeats itself, in part because history does. The impulses, ambitions, fantasies, and desires that drive human history are, at least in part, encoded in the human genome. And human history has, in turn, selected genomes that carry these impulses, ambitions, fantasies, and desires. ([Location 8315](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=8315)) - Tags: [[blue]] - Scientists divide. We discriminate. It is the inevitable occupational hazard of our profession that we must break the world into its constituent parts—genes, atoms, bytes—before making it whole again. We know of no other mechanism to understand the world: to create the sum of the parts, we must begin by dividing it into the parts of the sum. But there is a hazard implicit in this method. Once we perceive organisms—humans—as assemblages built from genes, environments, and gene-environment interactions, our view of humans is fundamentally changed. “No sane biologist believes that we are entirely the product of their genes,” Berg told me, “but once you bring genes into the picture, then our perception of ourselves can no longer be the same.” A whole assembled from the sum of the parts is different from the whole before it was broken into the parts. ([Location 8337](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=8337)) - Tags: [[blue]] - In 1990, writing about the Human Genome Project, the worm geneticist John Sulston wondered about the philosophical quandary raised by an intelligent organism that has “learned to read its own instructions.” But an infinitely deeper quandary is raised when an intelligent organism learns to write its own instructions. If genes determine the nature and fate of an organism, and if organisms now begin to determine the nature and fate of their genes, then a circle of logic closes on itself. Once we start thinking of genes as destiny, manifest, then it is inevitable to begin imagining the human genome as manifest destiny. ([Location 8451](https://readwise.io/to_kindle?action=open&asin=B017I25DCC&location=8451)) - Tags: [[blue]]