An Amazon Best Book of May 2016: In 2010, Siddhartha Mukherjee was awarded the Pulitzer Prize for his book The Emperor of All Maladies, a “biography” of cancer. Here, he follows up with a biography of the gene—and The Gene is just as informative, wise, and well-written as that first book. Mukherjee opens with a survey of how the gene first came to be conceptualized and understood, taking us through the thoughts of Aristotle, Darwin, Mendel, Thomas Morgan, and others; he finishes the section with a look at the case of Carrie Buck (to whom the book is dedicated), who eventually was sterilized in 1927 in a famous American eugenics case. Carrie Buck’s sterilization comes as a warning that informs the rest of the book. This is what can happen when we start tinkering with this most personal science and misunderstand the ethical implications of those tinkerings. Through the rest of The Gene, Mukherjee clearly and skillfully illustrates how the science has grown so much more advanced and complicated since the 1920s—we are developing the capacity to directly manipulate the human genome—and how the ethical questions have also grown much more complicated. We could ask for no wiser, more fascinating and talented writer to guide us into the future of our human heredity than Siddhartha Mukherjee. --Chris Schluep

"This is perhaps the greatest detective story ever told—a millennia-long search, led by a thousand explorers, from Aristotle to Mendel to Francis Collins, for the question marks at the center of every living cell. Like The Emperor of All Maladies, The Gene is prodigious, sweeping, and ultimately transcendent. If you’re interested in what it means to be human, today and in the tomorrows to come, you must read this book." -- Anthony Doerr, author of All the Light We Cannot See

"The Gene is a magnificent synthesis of the science of life, and forces all to confront the essence of that science as well as the ethical and philosophical challenges to our conception of what constitutes being human." -- Paul Berg, winner of the Nobel Prize in Chemistry

"Compelling... Highly recommended.", Booklist, starred review

“Sobering, humbling, and extraordinarily rich reading from a wise and gifted writer who sees how far we have come—but how much farther far we have to go to understand our human nature and destiny.”, Kirkus, starred review

"Mukherjee deftly relates the basic scientific facts about the way genes are believed to function, while making clear the aspects of genetics that remain unknown. He offers insight into both the scientific process and the sociology of science... By relating familial information, Mukherjee grounds the abstract in the personal to add power and poignancy to his excellent narrative.", Publishers Weekly, starred review

“A magisterial account of how human minds have laboriously, ingeniously picked apart what makes us tick. . . . [The Gene] will confirm [Mukherjee] as our era’s preeminent popular historian of medicine. The Gene boats an even more ambitious sweep of human endeavor than its predecessor. . . . Mukherjee punctuates his encyclopedic investigations of collective and individual heritability, and our closing in on the genetic technologies that will transform how we will shape our own genome, with evocative personal anecdotes, deft literary allusions, wonderfully apt metaphors, and an irrepressible intellectual brio.”, Ben Dickinson, Elle

“Magnificent…. The story [of the gene] has been told, piecemeal, in different ways, but never before with the scope and grandeur that Siddhartha Mukherjee brings to his new history… he views his subject panoptically, from a great and clarifying height, yet also intimately.”, James Gleick, New York Times Book Review

“Many of the same qualities that made The Emperor of All Maladies so pleasurable are in full bloom in The Gene. The book is compassionate, tautly synthesized, packed with unfamiliar details about familiar people.”, Jennifer Senior, The New York Times

“Mukherjee’s visceral and thought-provoking descriptions... clearly show what he is capable of, both as a writer and as a thinker.”, Matthew Cobb, Nature

“His topic is compelling. . . . And it couldn’t have come at a better time.”, Courtney Humphries, Boston Globe

Siddhartha Mukherjee is the author of The Emperor of All Maladies: A Biography of Cancer, winner of the 2011 Pulitzer Prize in general nonfiction, and The Laws of Medicine. He is the editor of Best Science Writing 2013. Mukherjee is an assistant professor of medicine at Columbia University and a cancer physician and researcher. A Rhodes scholar, he graduated from Stanford University, University of Oxford, and Harvard Medical School. He has published articles in Nature, The New England Journal of Medicine, The New York Times, and Cell. He lives in New York with his wife and daughters. Visit his website at: SiddharthaMukherjee.com

 

The Gene

The Walled Garden

The students of heredity, especially, understand all of their subject except their subject. They were, I suppose, bred and born in that brier-patch, and have really explored it without coming to the end of it. That is, they have studied everything but the question of what they are studying.

—G. K. Chesterton, Eugenics and Other Evils

Ask the plants of the earth, and they will teach you.

—Job 12:8

The monastery was originally a nunnery. The monks of Saint Augustine’s Order had once lived—as they often liked to grouse—in more lavish circumstances in the ample rooms of a large stone abbey on the top of a hill in the heart of the medieval city of Brno (Brno in Czech, Brünn in German). The city had grown around them over four centuries, cascading down the slopes and then sprawling out over the flat landscape of farms and meadowlands below. But the friars had fallen out of favor with Emperor Joseph II in 1783. The midtown real estate was far too valuable to house them, the emperor had decreed bluntly—and the monks were packed off to a crumbling structure at the bottom of the hill in Old Brno, the ignominy of the relocation compounded by the fact that they had been assigned to live in quarters originally designed for women. The halls had the vague animal smell of damp mortar, and the grounds were overgrown with grass, bramble, and weeds. The only perk of this fourteenth-century building—as cold as a meathouse and as bare as a prison—was a rectangular garden with shade trees, stone steps, and a long alley, where the monks could walk and think in isolation.

The friars made the best of the new accommodations. A library was restored on the second floor. A study room was connected to it and outfitted with pine reading desks, a few lamps, and a growing collection of nearly ten thousand books, including the latest works of natural history, geology, and astronomy (the Augustinians, fortunately, saw no conflict between religion and most science; indeed, they embraced science as yet another testament of the workings of the divine order in the world). A wine cellar was carved out below, and a modest refectory vaulted above it. One-room cells, with the most rudimentary wooden furniture, housed the inhabitants on the second floor.

In October 1843, a young man from Silesia, the son of two peasants, joined the abbey. He was a short man with a serious face, myopic, and tending toward portliness. He professed little interest in the spiritual life—but was intellectually curious, good with his hands, and a natural gardener. The monastery provided him with a home, and a place to read and learn. He was ordained on August 6, 1847. His given name was Johann, but the friars changed it to Gregor Johann Mendel.

For the young priest in training, life at the monastery soon settled into a predictable routine. In 1845, as part of his monastic education, Mendel attended classes in theology, history, and natural sciences at Brno’s Theological College. The tumult of 1848—the bloody populist revolutions that swept fiercely through France, Denmark, Germany, and Austria and overturned social, political, and religious orders—largely passed him by, like distant thunder. Nothing about Mendel’s early years suggested even the faintest glimmer of the revolutionary scientist who would later emerge. He was disciplined, plodding, deferential—a man of habits among men in habits. His only challenge to authority, it seemed, was his occasional refusal to wear the scholar’s cap to class. Admonished by his superiors, he politely complied.

In the summer of 1848, Mendel began work as a parish priest in Brno. He was, by all accounts, terrible at the job. “Seized by an unconquerable timidity,” as the abbot described it, Mendel was tongue-tied in Czech (the language of most parishioners), uninspiring as a priest, and too neurotic to bear the emotional brunt of the work among the poor. Later that year, he schemed a perfect way out: he applied for a job to teach mathematics, natural sciences, and elementary Greek at the Znaim High School. With a helpful nudge from the abbey, Mendel was selected—although there was a catch. Knowing that he had never been trained as a teacher, the school asked Mendel to sit for the formal examination in the natural sciences for high school teachers.

In the late spring of 1850, an eager Mendel took the written version of the exam in Brno. He failed—with a particularly abysmal performance in geology (“arid, obscure and hazy,” one reviewer complained of Mendel’s writing on the subject). On July 20, in the midst of an enervating heat wave in Austria, he traveled from Brno to Vienna to take the oral part of the exam. On August 16, he appeared before his examiners to be tested in the natural sciences. This time, his performance was even worse—in biology. Asked to describe and classify mammals, he scribbled down an incomplete and absurd system of taxonomy—omitting categories, inventing others, lumping kangaroos with beavers, and pigs with elephants. “The candidate seems to know nothing about technical terminology, naming all animals in colloquial German, and avoiding systematic nomenclature,” one of the examiners wrote. Mendel failed again.

In August, Mendel returned to Brno with his exam results. The verdict from the examiners had been clear: if Mendel was to be allowed to teach, he needed additional education in the natural sciences—more advanced training than the monastery library, or its walled garden, could provide. Mendel applied to the University of Vienna to pursue a degree in the natural sciences. The abbey intervened with letters and pleas; Mendel was accepted.

In the winter of 1851, Mendel boarded the train to enroll in his classes at the university. It was here that Mendel’s problems with biology—and biology’s problems with Mendel—would begin.



The night train from Brno to Vienna slices through a spectacularly bleak landscape in the winter—the farmlands and vineyards buried in frost, the canals hardened into ice-blue venules, the occasional farmhouse blanketed in the locked darkness of Central Europe. The river Thaya crosses the land, half-frozen and sluggish; the islands of the Danube come into view. It is a distance of only ninety miles—a journey of about four hours in Mendel’s time. But the morning of his arrival, it was as if Mendel had woken up in a new cosmos.

In Vienna, science was crackling, electric—alive. At the university, just a few miles from his back-alley boardinghouse on Invalidenstrasse, Mendel began to experience the intellectual baptism that he had so ardently sought in Brno. Physics was taught by Christian Doppler, the redoubtable Austrian scientist who would become Mendel’s mentor, teacher, and idol. In 1842, Doppler, a gaunt, acerbic thirty-nine-year-old, had used mathematical reasoning to argue that the pitch of sound (or the color of light) was not fixed, but depended on the location and velocity of the observer. Sound from a source speeding toward a listener would become compressed and register at a higher pitch, while sound speeding away would be heard with a drop in its pitch. Skeptics had scoffed: How could the same light, emitted from the same lamp, be registered as different colors by different viewers? But in 1845, Doppler had loaded a train with a band of trumpet players and asked them to hold a note as the train sped forward. As the audience on the platform listened in disbelief, a higher note came from the train as it approached, and a lower note emanated as it sped away.

Sound and light, Doppler argued, behaved according to universal and natural laws—even if these were deeply counterintuitive to ordinary viewers or listeners. Indeed, if you looked carefully, all the chaotic and complex phenomena of the world were the result of highly organized natural laws. Occasionally, our intuitions and perceptions might allow us to grasp these natural laws. But more commonly, a profoundly artificial experiment—loading trumpeters on a speeding train—might be necessary to understand and demonstrate these laws.

Doppler’s demonstrations and experiments captivated Mendel as much as they frustrated him. Biology, his main subject, seemed to be a wild, overgrown garden of a discipline, lacking any systematic organizing principles. Superficially, there seemed to be a profusion of order—or rather a profusion of Orders. The reigning discipline in biology was taxonomy, an elaborate attempt to classify and subclassify all living things into distinct categories: Kingdoms, Phylae, Classes, Orders, Families, Genera, and Species. But these categories, originally devised by the Swedish botanist Carl Linnaeus in the mid-1700s, were purely descriptive, not mechanistic. The system described how to categorize living things on the earth, but did not ascribe an underlying logic to its organization. Why, a biologist might ask, were living things categorized in this manner? What maintained its constancy or fidelity: What kept elephants from morphing into pigs, or kangaroos into beavers? What was the mechanism of heredity? Why, or how, did like beget like?



The question of “likeness” had preoccupied scientists and philosophers for centuries. Pythagoras, the Greek scholar—half scientist, half mystic—who lived in Croton around 530 BC, proposed one of the earliest and most widely accepted theories to explain the similarity between parents and their children. The core of Pythagoras’s theory was that hereditary information (“likeness”) was principally carried in male semen. Semen collected these instructions by coursing through a man’s body and absorbing mystical vapors from each of the individual parts (the eyes contributed their color, the skin its texture, the bones their length, and so forth). Over a man’s life, his semen grew into a mobile library of every part of the body—a condensed distillate of the self.

This self-information—seminal, in the most literal sense—was transmitted into a female body during intercourse. Once inside the womb, semen matured into a fetus via nourishment from the mother. In reproduction (as in any form of production) men’s work and women’s work were clearly partitioned, Pythagoras argued. The father provided the essential information to create a fetus. The mother’s womb provided nutrition so that this data could be transformed into a child. The theory was eventually called spermism, highlighting the central role of the sperm in determining all the features of a fetus.

In 458 BC, a few decades after Pythagoras’s death, the playwright Aeschylus used this odd logic to provide one of history’s most extraordinary legal defenses of matricide. The central theme of Aeschylus’s Eumenides is the trial of Orestes, the prince of Argos, for the murder of his mother, Clytemnestra. In most cultures, matricide was perceived as an ultimate act of moral perversion. In Eumenides, Apollo, chosen to represent Orestes in his murder trial, mounts a strikingly original argument: he reasons that Orestes’s mother is no more than a stranger to him. A pregnant woman is just a glorified human incubator, Apollo argues, an intravenous bag dripping nutrients through the umbilical cord into her child. The true forebear of all humans is the father, whose sperm carries “likeness.” “Not the true parent is the woman’s womb that bears the child,” Apollo tells a sympathetic council of jurors. “She doth but nurse the seed, new-sown. The male is parent. She for him—as stranger for a stranger—just hoards the germ of life.”

The evident asymmetry of this theory of inheritance—the male supplying all the “nature” and the female providing the initial “nurture” in her womb—didn’t seem to bother Pythagoras’s followers; indeed, they may have found it rather pleasing. Pythagoreans were obsessed with the mystical geometry of triangles. Pythagoras had learned the triangle theorem—that the length of the third side of a right-angled triangle can be deduced mathematically from the length of the other two sides—from Indian or Babylonian geometers. But the theorem became inextricably attached to his name (henceforth called the Pythagorean theorem), and his students offered it as proof that such secret mathematical patterns—“harmonies”—were lurking everywhere in nature. Straining to see the world through triangle-shaped lenses, Pythagoreans argued that in heredity too a triangular harmony was at work. The mother and the father were two independent sides and the child was the third—the biological hypotenuse to the parents’ two lines. And just as a triangle’s third side could arithmetically be derived from the two other sides using a strict mathematical formula, so was a child derived from the parents’ individual contributions: nature from father and nurture from mother.

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.



It took a mind as precise and analytical as Aristotle’s to systematically dismantle Pythagoras’s theory of heredity. Aristotle was not a particularly ardent champion of women, but he nevertheless believed in using evidence as the basis of theory building. He set about dissecting the merits and problems of “spermism” using experimental data from the biological world. The result, a compact treatise titled Generation of Animals, would serve as a foundational text for human genetics just as Plato’s Republic was a founding text for political philosophy.

Aristotle rejected the notion that heredity was carried exclusively in male semen or sperm. He noted, astutely, that children can inherit features from their mothers and grandmothers (just as they inherit features from their fathers and grandfathers), and that these features can even skip generations, disappearing for one generation and reappearing in the next. “And from deformed [parents] deformed [offspring] comes to be,” he wrote, “just as lame come to be from lame and blind from blind, and in general they resemble often the features that are against nature, and have inborn signs such as growths and scars. Some of such features have even been transmitted through three [generations]: for instance, someone who had a mark on his arm and his son was born without it, but his grandson had black in the same place, but in a blurred way. . . . In Sicily a woman committed adultery with a man from Ethiopia; the daughter did not become an Ethiopian, but her [grand]daughter did.” A grandson could be born with his grandmother’s nose or her skin color, without that feature being visible in either parent—a phenomenon virtually impossible to explain in terms of Pythagoras’s scheme of purely patrilineal heredity.

Aristotle challenged Pythagoras’s “traveling library” notion that semen collected hereditary information by coursing through the body and obtaining secret “instructions” from each individual part. “Men generate before they yet have certain characters, such as a beard or grey hair,” Aristotle wrote perceptively—but they pass on those features to their children. Occasionally, the feature transmitted through heredity was not even corporeal: a manner of walking, say, or a way of staring into space, or even a state of mind. Aristotle argued that such traits—not material to start with—could not materialize into semen. And finally, and perhaps more obviously, he attacked Pythagoras’s scheme with the most self-evident of arguments: it could not possibly account for female anatomy. How could a father’s sperm “absorb” the instructions to produce his daughter’s “generative parts,” Aristotle asked, when none of these parts was to be found anywhere in the father’s body? Pythagoras’s theory could explain every aspect of genesis except the most crucial one: genitals.

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.”

Female semen, in contrast, contributed the physical raw material for the fetus—wood for the carpenter, or mortar for the building: the stuff and the stuffing of life. Aristotle argued that the actual material provided by females was menstrual blood. Male semen sculpted menstrual blood into the shape of a child (the claim might sound outlandish today, but here too Aristotle’s meticulous logic was at work. Since the disappearance of menstrual blood is coincident with conception, Aristotle assumed that the fetus must be made from it).

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.



But if heredity was transmitted as information, then how was that information encoded? The word code comes from the Latin caudex, the wooden pith of a tree on which scribes carved their writing. What, then, was the caudex of heredity? What was being transcribed, and how? How was the material packaged and transported from one body to the next? Who encrypted the code, and who translated it, to create a child?

The most inventive solution to these questions was the simplest: it dispensed of code altogether. Sperm, this theory argued, already contained a minihuman—a tiny fetus, fully formed, shrunken and curled into a minuscule package and waiting to be progressively inflated into a baby. Variations of this theory appear in medieval myths and folklore. In the 1520s, the Swiss-German alchemist Paracelsus used the minihuman-in-sperm theory to suggest that human sperm, heated with horse dung and buried in mud for the forty weeks of normal conception, would eventually grow into a human, although with some monstrous characteristics. The conception of a normal child was merely the transfer of this minihuman—the homunculus—from the father’s sperm into the mother’s womb. In the womb, the minihuman was expanded to the size of the fetus. There was no code; there was only miniaturization.

The peculiar charm of this idea—called preformation—was that it was infinitely recursive. Since the homunculus had to mature and produce its own children, it had to have preformed mini-homunculi lodged inside it—tiny humans encased inside humans, like an infinite series of Russian dolls, a great chain of beings that stretched all the way backward from the present to the first man, to Adam, and forward into the future. For medieval Christians, the existence of such a chain of humans provided a most powerful and original understanding of original sin. Since all future humans were encased within all humans, each of us had to have been physically present inside Adam’s body—“floating . . . in our First Parent’s loins,” as one theologian described—during his crucial moment of sin. Sinfulness, therefore, was embedded within us thousands of years before we were born—from Adam’s loins directly to his line. All of us bore its taint—not because our distant ancestor had been tempted in that distant garden, but because each of us, lodged in Adam’s body, had actually tasted the fruit.

The second charm of preformation was that it dispensed of the problem of de-encryption. Even if early biologists could fathom encryption—the conversion of a human body into some sort of code (by osmosis, à la Pythagoras)—the reverse act, deciphering that code back into a human being, completely boggled the mind. How could something as complex as a human form emerge out of the union of sperm and egg? The homunculus dispensed of this conceptual problem. If a child came already preformed, then its formation was merely an act of expansion—a biological version of a blowup doll. No key or cipher was required for the deciphering. The genesis of a human being was just a matter of adding water.

The theory was so seductive—so artfully vivid—that even the invention of the microscope was unable to deal the expected fatal blow to the homunculus. In 1694, Nicolaas Hartsoeker, the Dutch physicist and microscopist, conjured a picture of such a minibeing, its enlarged head twisted in fetal position and curled into the head of a sperm. In 1699, another Dutch microscopist claimed to have found homuncular creatures floating abundantly in human sperm. As with any anthropomorphic fantasy—finding human faces on the moon, say—the theory was only magnified by the lenses of imagination: pictures of homunculi proliferated in the seventeenth century, with the sperm’s tail reconceived into a filament of human hair, or its cellular head visualized as a tiny human skull. By the end of the seventeenth century, preformation was considered the most logical and consistent explanation for human and animal heredity. Men came from small men, as large trees came from small cuttings. “In nature there is no generation,” the Dutch scientist Jan Swammerdam wrote in 1669, “but only propagation.”



But not everyone could be convinced that miniature humans were infinitely encased inside humans. The principal challenge to preformation was the idea that something had to happen during embryogenesis that led to the formation of entirely new parts in the embryo. Humans did not come pre-shrunk and premade, awaiting only expansion. They had to be generated from scratch, using specific instructions locked inside the sperm and egg. Limbs, torsos, brains, eyes, faces—even temperaments or propensities that were inherited—had to be created anew each time an embryo unfurled into a human fetus. Genesis happened . . . well—by genesis.

By what impetus, or instruction, was the embryo, and the final organism, generated from sperm and egg? In 1768, the Berlin embryologist Caspar Wolff tried to finesse an answer by concocting a guiding principle—vis essentialis corporis, as he called it—that progressively shepherded the maturation of a fertilized egg into a human form. Like Aristotle, Wolff imagined that the embryo contained some sort of encrypted information—code—that was not merely a miniature version of a human, but instructions to make a human from scratch. But aside from inventing a Latinate name for a vague principle, Wolff could provide no further specifics. The instructions, he argued obliquely, were blended together in the fertilized egg. The vis essentialis then came along, like an invisible hand, and molded the formation of this mass into a human form.



While biologists, philosophers, Christian scholars, and embryologists fought their way through vicious debates between preformation and the “invisible hand” throughout much of the eighteenth century, a casual observer may have been forgiven for feeling rather unimpressed by it all. This was, after all, stale news. “The opposing views of today were in existence centuries ago,” a nineteenth-century biologist complained, rightfully. Indeed, preformation was largely a restatement of Pythagoras’s theory—that sperm carried all the information to make a new human. And the “invisible hand” was, in turn, merely a gilded variant of Aristotle’s idea—that heredity was carried in the form of messages to create materials (it was the “hand” that carried the instructions to mold an embryo).

In time, both the theories would be spectacularly vindicated, and spectacularly demolished. Both Aristotle and Pythagoras were partially right and partially wrong. But in the early 1800s, it seemed as if the entire field of heredity and embryogenesis had reached a conceptual impasse. The world’s greatest biological thinkers, having pored over the problem of heredity, had scarcely advanced the field beyond the cryptic musings of two men who had lived on two Greek islands two thousand years earlier.