The Violinist's Thumb

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In accordance with the U.S. Copyright Act of 1976, the scanning, uploading, and electronic sharing of any part of this book without the permission of the publisher is unlawful piracy and theft of the author's intellectual property. If you would like to use material from the book (other than for review purposes), prior written permission must be obtained by contacting the publisher at permissions@hbgusa.com. Thank you for your support of the author's rights.

Acrostic: n., an incognito message formed by stringing together the initial letters of lines or paragraphs or other units of composition in a work.

N.B.: I've hidden a DNA-related acrostic in The Violinist's Thumb—a genetic "Easter egg," if you will. If you decode this message, e-mail me through my website (http://samkean.com/contact). Or if you can't figure it out, e-mail me anyway and I'll reveal the answer.

Introduction

This might as well come out up front, first paragraph. This is a book about DNA—about digging up stories buried in your DNA for thousands, even millions of years, and using DNA to solve mysteries about human beings whose solutions once seemed lost forever. And yes, I'm writing this book despite the fact that my father's name is Gene. As is my mother's name. Gene and Jean. Gene and Jean Kean. Beyond being singsong absurd, my parents' names led to a lot of playground jabs over the years: my every fault and foible was traced to "my genes," and when I did something idiotic, people smirked that "my genes made me do it." That my parents' passing on their genes necessarily involved sex didn't help. The taunts were doubly barbed, utterly unanswerable.

Bottom line is, I dreaded learning about DNA and genes in science classes growing up because I knew some witticism would be coming within about two seconds of the teacher turning her back. And if it wasn't coming, some wiseacre was thinking it. Some of that Pavlovian trepidation always stayed with me, even when (or especially when) I began to grasp how potent a substance DNA is. I got over the gibes by high school, but the word gene still evoked a lot of simultaneous responses, some agreeable, some not.

On the one hand, DNA excites me. There's no bolder topic in science than genetics, no field that promises to push science forward to the same degree. I don't mean just the common (and commonly overblown) promises of medical cures, either. DNA has revitalized every field in biology and remade the very study of human beings. At the same time, whenever someone starts digging into our basic human biology, we resist the intrusion—we don't want to be reduced to mere DNA. And when someone talks about tinkering with that basic biology, it can be downright frightening.

More ambiguously, DNA offers a powerful tool for rooting through our past: biology has become history by other means. Even in the past decade or so, genetics has opened up a whole Bible's worth of stories whose plotlines we assumed had vanished—either too much time had lapsed, or too little fossil or anthropological evidence remained to piece together a coherent narrative. It turns out we were carrying those stories with us the entire time, trillions of faithfully recorded texts that the little monks in our cells transcribed every hour of every day of our DNA dark age, waiting for us to get up to speed on the language. These stories include the grand sagas of where we came from and how we evolved from primordial muck into the most dominant species the planet has known. But the stories come home in surprisingly individual ways, too.

If I could have had one mulligan in school (besides a chance to make up safer names for my parents), I'd have picked a different instrument to play in band. It wasn't because I was the only boy clarinetist in the fourth, fifth, sixth, seventh, eighth, and ninth grades (or not only because of that). It was more because I felt so clumsy working all the valves and levers and blowholes on the clarinet. Nothing to do with a lack of practice, surely. I blamed the deficit on my double-jointed fingers and splayed hitchhiker thumbs. Playing the clarinet wound my fingers into such awkward braids that I constantly felt a need to crack my knuckles, and they'd throb a little. Every blue moon one thumb would even get stuck in place, frozen in extension, and I had to work the joint free with my other hand. My fingers just didn't do what the better girl clarinetists' could. My problems were inherited, I told myself, a legacy of my parents' gene stock.

After quitting band, I had no reason to reflect on my theory about manual dexterity and musical ability until a decade later, when I learned the story of violinist Niccolò Paganini, a man so gifted he had to shake off rumors his whole life that he'd sold his soul to Satan for his talent. (His hometown church even refused to bury his body for decades after his death.) It turns out Paganini had made a pact with a subtler master, his DNA. Paganini almost certainly had a genetic disorder that gave him freakishly flexible fingers. His connective tissues were so rubbery that he could pull his pinky out sideways to form a right angle to the rest of his hand. (Try this.) He could also stretch his hands abnormally wide, an incomparable advantage when playing the violin. My simple hypothesis about people "being born" to play (or not play) certain instruments seemed justified. I should have quit when ahead. I kept investigating and found out that Paganini's syndrome probably caused serious health problems, as joint pain, poor vision, weakness of breath, and fatigue dogged the violinist his whole life. I whimpered about stiff knuckles during early a.m. marching-band practice, but Paganini frequently had to cancel shows at the height of his career and couldn't perform in public during the last years of his life. In Paganini, a passion for music had united with a body perfectly tuned to take advantage of its flaws, possibly the greatest fate a human could hope for. Those flaws then hastened his death. Paganini may not have chosen his pact with his genes, but he was in one, like all of us, and the pact both made and unmade him.

DNA wasn't done telling its stories to me. Some scientists have retroactively diagnosed Charles Darwin, Abraham Lincoln, and Egyptian pharaohs with genetic disorders. Other scientists have plumbed DNA itself to articulate its deep linguistic properties and surprising mathematical beauty. In fact, just as I had crisscrossed from band to biology to history to math to social studies in high school, so stories about DNA began popping up in all sorts of contexts, linking all sorts of disparate subjects. DNA informed stories about people surviving nuclear bombs, and stories about the untimely ends of explorers in the Arctic. Stories about the near extinction of the human species, or pregnant mothers giving cancer to their unborn children. Stories where, as with Paganini, science illuminates art, and even stories where—as with scholars tracing genetic defects through portraiture—art illuminates science.

One fact you learn in biology class but don't appreciate at first is the sheer length of the DNA molecule. Despite being packed into a tiny closet in our already tiny cells, DNA can unravel to extraordinary distances. There's enough DNA in some plant cells to stretch three hundred feet; enough DNA in one human body to stretch roughly from Pluto to the sun and back; enough DNA on earth to stretch across the known universe many, many times. And the further I pursued the stories of DNA, the more I saw that its quality of stretching on and on—of unspooling farther and farther out, and even back, back through time—was intrinsic to DNA. Every human activity leaves a forensic trace in our DNA, and whether that DNA records stories about music or sports or Machiavellian microbes, those tales tell, collectively, a larger and more intricate tale of the rise of human beings on Earth: why we're one of nature's most absurd creatures, as well as its crowning glory.

Underlying my excitement, though, is the other side of genes: the trepidation. While researching this book, I submitted my DNA to a genetic testing service, and despite the price tag ($414), I did so in a frivolous state of mind. I knew personal genomic testing has serious shortcomings, and even when the science is solid, it's often not that helpful. I might learn from my DNA that I have green eyes, but then again I do own a mirror. I might learn I don't metabolize caffeine well, but I've had plenty of jittery nights after a late Coke. Besides, it was hard to take the DNA-submission process seriously. A plastic vial with a candy-corn orange lid arrived in the mail, and the instructions told me to massage my cheeks with my knuckles to work some cells loose inside my mouth. I then hocked into the tube repeatedly until I filled it two-thirds full of saliva. That took ten minutes, since the instructions said in all seriousness that it couldn't be just any saliva. It had to be the good, thick, syrupy stuff; as with a draft beer, there shouldn't be much foam. The next day I mailed the genetic spittoon off, hoping for a nice surprise about my ancestry. I didn't engage in any sober reflection until I went to register my test online and read the instructions about redacting sensitive or scary information. If your family has a history of breast cancer or Alzheimer's or other diseases—or if the mere thought of having them frightens you—the testing service lets you block that information. You can tick a box and keep it secret from even yourself. What caught me short was the box for Parkinson's disease. One of the earliest memories I have, and easily the worst of those early memories, is wandering down the hallway of my grandma's house and poking my head into the room where my grandpa, laid low by Parkinson's, lived out his days.

When he was growing up, people always told my father how much he looked like my grandpa—and I got similar comments about looking like my old man. So when I wandered into that room off the hallway and saw a white-haired version of my father propped in a bed with a metal safety rail, I saw myself by extension. I remember lots of white—the walls, the carpet, the sheets, the open-backed smock he wore. I remember him pitched forward to the point of almost tipping over, his smock loose and a fringe of white hair hanging straight down.

I'm not sure whether he saw me, but when I hesitated on the threshold, he moaned and began trembling, which made his voice quake. My grandpa was lucky in some ways; my grandma, a nurse, took care of him at home, and his children visited regularly. But he'd regressed mentally and physically. I remember most of all the thick, syrupy string of saliva pendulous on his chin, full of DNA. I was five or so, too young to understand. I'm still ashamed that I ran.

Now, strangers—and worse, my own self—could peek at whether the string of self-replicating molecules that might have triggered Parkinson's in my grandfather was lurking in my cells, too. There was a good chance not. My grandpa's genes had been diluted by my grandma's genes in Gene, whose genes had in turn been diluted in me by Jean's. But the chance was certainly real. I could face any of the cancers or other degenerative diseases I might be susceptible to. Not Parkinson's. I blacked the data out.

Personal stories like that are as much a part of genetics as all the exciting history—perhaps more so, since all of us have at least one of these stories buried inside us. That's why this book, beyond relating all the historical tales, builds on those tales and links them to work being done on DNA today, and work likely to be done tomorrow. This genetics research and the changes it will bring have been compared to a shifting ocean tide, huge and inevitable. But its consequences will arrive at the shore where we're standing not as a tsunami but as tiny waves. It's the individual waves we'll feel, one by one, as the tide crawls up the shore, no matter how far back we think we can stand.

Still, we can prepare ourselves for their arrival. As some scientists recognize, the story of DNA has effectively replaced the old college Western Civ class as the grand narrative of human existence. Understanding DNA can help us understand where we come from and how our bodies and minds work, and understanding the limits of DNA also helps us understand how our bodies and minds don't work. To a similar degree, we'll have to prepare ourselves for whatever DNA says (and doesn't say) about intractable social problems like gender and race relations, or whether traits like aggression and intelligence are fixed or flexible. We'll also have to decide whether to trust eager thinkers who, while acknowledging that we don't understand completely how DNA works, already talk about the opportunity, even the obligation, to improve on four billion years of biology. To this point of view, the most remarkable story about DNA is that our species survived long enough to (potentially) master it.

The history in this book is still being constructed, and I structured The Violinist's Thumb so that each chapter provides the answer to a single question. The overarching narrative starts in the remote microbial past, moves on to our animal ancestries, lingers over primates and hominid competitors like Neanderthals, and culminates with the emergence of modern, cultured human beings with flowery language and hypertrophied brains. But as the book advances toward the final section, the questions have not been fully resolved. Things remain uncertain—especially the question of how this grand human experiment of uprooting everything there is to know about our DNA will turn out.

PART I

A, C, G, T, and You

How to Read a Genetic Score

1

Genes, Freaks, DNA

How Do Living Things Pass Down Traits to Their Children?

Chills and flames, frost and inferno, fire and ice. The two scientists who made the first great discoveries in genetics had a lot in common—not least the fact that both died obscure, mostly unmourned and happily forgotten by many. But whereas one's legacy perished in fire, the other's succumbed to ice.

The blaze came during the winter of 1884, at a monastery in what's now the Czech Republic. The friars spent a January day emptying out the office of their deceased abbot, Gregor Mendel, ruthlessly purging his files, consigning everything to a bonfire in the courtyard. Though a warm and capable man, late in life Mendel had become something of an embarrassment to the monastery, the cause for government inquiries, newspaper gossip, even a showdown with a local sheriff. (Mendel won.) No relatives came by to pick up Mendel's things, and the monks burned his papers for the same reason you'd cauterize a wound—to sterilize, and stanch embarrassment. No record survives of what they looked like, but among those documents were sheaves of papers, or perhaps a lab notebook with a plain cover, probably coated in dust from disuse. The yellowed pages would have been full of sketches of pea plants and tables of numbers (Mendel adored numbers), and they probably didn't kick up any more smoke and ash than other papers when incinerated. But the burning of those papers—burned on the exact spot where Mendel had kept his greenhouse years before—destroyed the only original record of the discovery of the gene.

The chills came during that same winter of 1884—as they had for many winters before, and would for too few winters after. Johannes Friedrich Miescher, a middling professor of physiology in Switzerland, was studying salmon, and among his other projects he was indulging a long-standing obsession with a substance—a cottony gray paste—he'd extracted from salmon sperm years before. To keep the delicate sperm from perishing in the open air, Miescher had to throw the windows open to the cold and refrigerate his lab the old-fashioned way, exposing himself day in and day out to the Swiss winter. Getting any work done required superhuman focus, and that was the one asset even people who thought little of Miescher would admit he had. (Earlier in his career, friends had to drag him from his lab bench one afternoon to attend his wedding; the ceremony had slipped his mind.) Despite being so driven, Miescher had pathetically little to show for it—his lifetime scientific output was meager. Still, he kept the windows open and kept shivering year after year, though he knew it was slowly killing him. And he still never got to the bottom of that milky gray substance, DNA.

DNA and genes, genes and DNA. Nowadays the words have become synonymous. The mind rushes to link them, like Gilbert and Sullivan or Watson and Crick. So it seems fitting that Miescher and Mendel discovered DNA and genes almost simultaneously in the 1860s, two monastic men just four hundred miles apart in the German-speaking span of middle Europe. It seems more than fitting; it seems fated.

But to understand what DNA and genes really are, we have to decouple the two words. They're not identical and never have been. DNA is a thing—a chemical that sticks to your fingers. Genes have a physical nature, too; in fact, they're made of long stretches of DNA. But in some ways genes are better viewed as conceptual, not material. A gene is really information—more like a story, with DNA as the language the story is written in. DNA and genes combine to form larger structures called chromosomes, DNA-rich volumes that house most of the genes in living things. Chromosomes in turn reside in the cell nucleus, a library with instructions that run our entire bodies.

All these structures play important roles in genetics and heredity, but despite the near-simultaneous discovery of each in the 1800s, no one connected DNA and genes for almost a century, and both discoverers died uncelebrated. How biologists finally yoked genes and DNA together is the first epic story in the science of inheritance, and even today, efforts to refine the relationship between genes and DNA drive genetics forward.

Mendel and Miescher began their work at a time when folk theories—some uproarious or bizarre, some quite ingenious, in their way—dominated most people's thinking about heredity, and for centuries these folk theories had colored their views about why we inherit different traits.

Everyone knew on some level of course that children resemble parents. Red hair, baldness, lunacy, receding chins, even extra thumbs, could all be traced up and down a genealogical tree. And fairy tales—those codifiers of the collective unconscious—often turned on some wretch being a "true" prince(ss) with a royal bloodline, a biological core that neither rags nor an amphibian frame could sully.

That's mostly common sense. But the mechanism of heredity—how exactly traits got passed from generation to generation—baffled even the most intelligent thinkers, and the vagaries of this process led to many of the wilder theories that circulated before and even during the 1800s. One ubiquitous folk theory, "maternal impressions," held that if a pregnant woman saw something ghoulish or suffered intense emotions, the experience would scar her child. One woman who never satisfied an intense prenatal craving for strawberries gave birth to a baby covered with red, strawberry-shaped splotches. The same could happen with bacon. Another woman bashed her head on a sack of coal, and her child had half, but only half, a head of black hair. More direly, doctors in the 1600s reported that a woman in Naples, after being startled by sea monsters, bore a son covered in scales, who ate fish exclusively and gave off fishy odors. Bishops told cautionary tales of a woman who seduced her actor husband backstage in full costume. He was playing Mephistopheles; they had a child with hooves and horns. A beggar with one arm spooked a woman into having a one-armed child. Pregnant women who pulled off crowded streets to pee in churchyards invariably produced bed wetters. Carrying fireplace logs about in your apron, next to the bulging tummy, would produce a grotesquely well-hung lad. About the only recorded happy case of maternal impressions involved a patriotic woman in Paris in the 1790s whose son had a birthmark on his chest shaped like a Phrygian cap—those elfish hats with a flop of material on top. Phrygian caps were symbols of freedom to the new French republic, and the delighted government awarded her a lifetime pension.

Much of this folklore intersected with religious belief, and people naturally interpreted serious birth defects—cyclopean eyes, external hearts, full coats of body hair—as back-of-the-Bible warnings about sin, wrath, and divine justice. One example from the 1680s involved a cruel bailiff in Scotland named Bell, who arrested two female religious dissenters, lashed them to poles near the shore, and let the tide swallow them. Bell added insult by taunting the women, then drowned the younger, more stubborn one with his own hands. Later, when asked about the murders, Bell always laughed, joking that the women must be having a high time now, scuttling around among the crabs. The joke was on Bell: after he married, his children were born with a severe defect that twisted their forearms into two awful pincers. These crab claws proved highly heritable to their children and grandchildren, too. It didn't take a biblical scholar to see that the iniquity of the father had been visited upon the children, unto the third and fourth generations. (And beyond: cases popped up in Scotland as late as 1900.)

If maternal impressions stressed environmental influences, other theories of inheritance had strong congenital flavors. One, preformationism, grew out of the medieval alchemists' quest to create a homunculus, a miniature, even microscopic, human being. Homunculi were the biological philosopher's stone, and creating one showed that an alchemist possessed the power of gods. (The process of creation was somewhat less dignified. One recipe called for fermenting sperm, horse dung, and urine in a pumpkin for six weeks.) By the late 1600s, some protoscientists had stolen the idea of the homunculus and were arguing that one must live inside each female egg cell. This neatly did away with the question of how living embryos arose from seemingly dead blobs of matter. Under preformationist theory, such spontaneous generation wasn't necessary: homuncular babies were indeed preformed and merely needed a trigger, like sperm, to grow. This idea had only one problem: as critics pointed out, it introduced an infinite regress, since a woman necessarily had to have all her future children, as well as their children, and their children, stuffed inside her, like Russian matryoshka nesting dolls. Indeed, adherents of "ovism" could only deduce that God had crammed the entire human race into Eve's ovaries on day one. (Or rather, day six of Genesis.) "Spermists" had it even worse—Adam must have had humanity entire sardined into his even tinier sperms. Yet after the first microscopes appeared, a few spermists tricked themselves into seeing tiny humans bobbing around in puddles of semen. Both ovism and spermism gained credence in part because they explained original sin: we all resided inside Adam or Eve during their banishment from Eden and therefore all share the taint. But spermism also introduced theological quandaries—for what happened to the endless number of unbaptized souls that perished every time a man ejaculated?

However poetic or deliciously bawdy these theories were, biologists in Miescher's day scoffed at them as old wives' tales. These men wanted to banish wild anecdotes and vague "life forces" from science and ground all heredity and development in chemistry instead.

Miescher hadn't originally planned to join this movement to demystify life. As a young man he had trained to practice the family trade, medicine, in his native Switzerland. But a boyhood typhoid infection had left him hard of hearing and unable to use a stethoscope or hear an invalid's bedside bellyaching. Miescher's father, a prominent gynecologist, suggested a career in research instead. So in 1868 the young Miescher moved into a lab run by the biochemist Felix Hoppe-Seyler, in Tübingen, Germany. Though headquartered in an impressive medieval castle, Hoppe-Seyler's lab occupied the royal laundry room in the basement; he found Miescher space next door, in the old kitchen.

Hoppe-Seyler wanted to catalog the chemicals present in human blood cells. He had already investigated red blood cells, so he assigned white ones to Miescher—a fortuitous decision for his new assistant, since white blood cells (unlike red ones) contain a tiny internal capsule called a nucleus. At the time, most scientists ignored the nucleus—it had no known function—and quite reasonably concentrated on the cytoplasm instead, the slurry that makes up most of a cell's volume. But the chance to analyze something unknown appealed to Miescher.

Friedrich Miescher (inset) discovered DNA in this laboratory, a renovated kitchen in the basement of a castle in Tübingen, Germany. (University of Tübingen library)

To study the nucleus, Miescher needed a steady supply of white blood cells, so he approached a local hospital. According to legend, the hospital catered to veterans who'd endured gruesome battlefield amputations and other mishaps. Regardless, the clinic did house many chronic patients, and each day a hospital orderly collected pus-soaked bandages and delivered the yellowed rags to Miescher. The pus often degraded into slime in the open air, and Miescher had to smell each suppurated-on cloth and throw out the putrid ones (most of them). But the remaining "fresh" pus was swimming with white blood cells.

Eager to impress—and, in truth, doubtful of his own talents—Miescher threw himself into studying the nucleus, as if sheer labor would make up for any shortcomings. A colleague later described him as "driven by a demon," and Miescher exposed himself daily to all manner of chemicals in his work. But without this focus, he probably wouldn't have discovered what he did, since the key substance inside the nucleus proved elusive. Miescher first washed his pus in warm alcohol, then acid extract from a pig's stomach, to dissolve away the cell membranes. This allowed him to isolate a gray paste. Assuming it was protein, he ran tests to identify it. But the paste resisted protein digestion and, unlike any known protein, wouldn't dissolve in salt water, boiling vinegar, or dilute hydrochloric acid. So he tried elementary analysis, charring it until it decomposed. He got the expected elements, carbon, hydrogen, oxygen, and nitrogen, but also discovered 3 percent phosphorus, an element proteins lack. Convinced he'd found something unique, he named the substance "nuclein"—what later scientists called deoxyribonucleic acid, or DNA.

Miescher polished off the work in a year, and in autumn 1869 stopped by the royal laundry to show Hoppe-Seyler. Far from rejoicing, the older scientist screwed up his brow and expressed his doubts that the nucleus contained any sort of special, nonproteinaceous substance. Miescher had made a mistake, surely. Miescher protested, but Hoppe-Seyler insisted on repeating the young man's experiments—step by step, bandage by bandage—before allowing him to publish. Hoppe-Seyler's condescension couldn't have helped Miescher's confidence (he never worked so quickly again). And even after two years of labor vindicated Miescher, Hoppe-Seyler insisted on writing a patronizing editorial to accompany Miescher's paper, in which he backhandedly praised Miescher for "enhanc[ing] our understanding… of pus." Nevertheless Miescher did get credit, in 1871, for discovering DNA.