The Violinist's Thumb: And Other Lost Tales of Love, War, and Genius, as Written by Our Genetic Code

by Sam Kean

  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 prominen
t 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.

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

  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.

  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.

  Some parallel discoveries quickly illuminated more about Miescher’s molecule. Most important, a German protégé of Hoppe-Seyler’s determined that nuclein contained multiple types of smaller constituent molecules. These included phosphates and sugars (the eponymous “deoxyribose” sugars), as well as four ringed chemicals now called nucleic “bases”—adenine, cytosine, guanine, and thymine. Still, no one knew how these parts fit together, and this jumble made DNA seem strangely heterogeneous and incomprehensible.

  (Scientists now know how all these parts contribute to DNA. The molecule forms a double helix, which looks like a ladder twisted into a corkscrew. The supports of the ladder are strands made of alternating phosphates and sugars. The ladder’s rungs—the most important part—are each made of two nucleic bases, and these bases pair up in specific ways: adenine, A, always bonds with thymine, T; cytosine, C, always bonds with guanine, G. [To remember this, notice that the curvaceous letters C and G pair-bond, as do angular A and T.])

  Meanwhile DNA’s reputation was bolstered by other discoveries. Scientists in the later 1800s determined that whenever cells divide in two, they carefully divvy up their chromosomes. This hinted that chromosomes were important for something, because otherwise cells wouldn’t bother. Another group of scientists determined that chromosomes are passed whole and intact from parent to child. Yet another German chemist then discovered that chromosomes were mostly made up of none other than DNA. From this constellation of findings—it took a little imagination to sketch in the lines and see a bigger picture—a small number of scientists realized that DNA might play a direct role in heredity. Nuclein was intriguing people.

  Miescher lucked out, frankly, when nuclein became a respectable object of inquiry; his career had stalled otherwise. After his stint in Tübingen, he moved home to Basel, but his new institute refused him his own lab—he got one corner in a common room and had to carry out chemical analyses in an old hallway. (The castle kitchen was looking pretty good suddenly.) His new job also required teaching. Miescher had an aloof, even frosty demeanor—he was someone never at ease around people—and although he labored over lectures, he proved a pedagogical disaster: students remember him as “insecure, restless… myopic… difficult to understand, [and] fidgety.” We like to think of scientific heroes as electric personalities, but Miescher lacked even rudimentary charisma.

  Given his atrocious teaching, which further eroded his self-esteem, Miescher rededicated himself to research. Upholding what one observer called his “fetish of examining objectionable fluids,” Miescher transferred his DNA allegiance from pus to semen. The sperm in semen were basically nuclein-tipped missiles and provided loads of DNA without much extraneous cytoplasm. Miescher also had a convenient source of sperm in the hordes of salmon that clogged the river Rhine near his university every autumn and winter. During spawning season, salmon testes grow like tumors, swelling twenty times larger than normal and often topping a pound each. To collect salmon, Miescher could practically dangle a fishing line from his office window, and by squeezing their “ripe” testes through cheesecloth, he isolated millions of bewildered little swimmers. The downside was that salmon sperm deteriorates at anything close to comfortable temperatures. So Miescher had to arrive at his bench in the chilly early hours before dawn, prop the windows open, and drop the temperature to around 35°F before working. And because of a stingy budget, when his laboratory glassware broke, he sometimes had to pilfer his ever-loving wife’s fine china to finish experiments.

  From this work, as well as his colleagues’ work with other cells, Miescher concluded that all cell nuclei contain DNA. In fact he proposed redefining cell nuclei—which come in a variety of sizes and shapes—strictly as containers for DNA. Though he wasn’t greedy about his reputation, this might have been a last stab at glory for Miescher. DNA might still have turned out to be relatively unimportant, and in that case, he would have at least figured out what the mysterious nucleus did. But it wasn’t to be. Though we now know Miescher was largely right in defining the nucleus, other scientists balked at his admittedly premature suggestion; there just wasn’t enough proof. And even if they bought that, they wouldn’t grant Miescher’s next, more self-serving claim: that DNA influenced heredity. It didn’t help that Miescher had no idea how DNA did so. Like many scientists then, he doubted that sperm injected anything into eggs, partly because he assumed (echoes of the homunculus here) that eggs already contained the full complement of parts needed for life. Rather, he imagined that sperm nuclein acted as a sort of chemical defibrillator and jump-started eggs. Unfortunately Miescher had little
time to explore or defend such ideas. He still had to lecture, and the Swiss government piled “thankless and tedious” tasks onto him, like preparing reports on nutrition in prisons and elementary schools. The years of working through Swiss winters with the windows open also did a number on his health, and he contracted tuberculosis. He ended up giving up DNA work altogether.

  Meanwhile other scientists’ doubts about DNA began to solidify, in their minds, into hard opposition. Most damning, scientists discovered that there was more to chromosomes than phosphate-sugar backbones and A-C-G-T bases. Chromosomes also contained protein nuggets, which seemed more likely candidates to explain chemical heredity. That’s because proteins were composed of twenty different subunits (called amino acids). Each of these subunits could serve as one “letter” for writing chemical instructions, and there seemed to be enough variety among these letters to explain the dazzling diversity of life itself. The A, C, G, and T of DNA seemed dull and simplistic in comparison, a four-letter pidgin alphabet with limited expressive power. As a result, most scientists decided that DNA stored phosphorus for cells, nothing more.