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

by Sam Kean

  Although pleased with the work—it earned her and Creighton bios in, well, American Men of Science—McClintock wanted more. She wanted to study not only chromosomes themselves but how chromosomes changed and mutated, and how those changes built complex organisms with different roots and colors and leaves. Unfortunately, as she tried to set up a lab, social circumstances conspired against her. Like the priesthood, universities at the time offered full professorships only to men (except in home ec), and Cornell had no intention of excepting McClintock. She left reluctantly in 1936 and bounced about, working with Morgan out in California for a spell, then taking research positions in Missouri and Germany. She hated both places.

  Truth be told, McClintock had other troubles beyond being the wrong gender. Not exactly the bubbly sort, she’d earned a reputation as sour and uncollegial—she’d once scooped a colleague by tackling his research problem behind his back and publishing her results before he finished. Equally problematic, McClintock worked on corn.

  Yes, there was money in corn genetics, since corn was a food crop. (One leading American geneticist, Henry Wallace—future vice president to FDR—made his fortune running a seed company.) Corn also had a scientific pedigree, as Darwin and Mendel had both studied it. Ag scientists even showed an interest in corn mutations: when the United States began exploding nukes at Bikini Atoll in 1946, government scientists placed corn seed beneath the airbursts to study how nuclear fallout affected maize.

  McClintock, though, pooh-poohed the traditional ends of corn research, like bigger yields and sweeter kernels. Corn was a means to her, a vehicle to study general inheritance and development. Unfortunately, corn had serious disadvantages for such work. It grew achingly slowly, and its capricious chromosomes often snapped, or grew bulges, or fused, or randomly doubled. McClintock savored the complexity, but most geneticists wanted to avoid these headaches. They trusted McClintock’s work—no one matched her on a microscope—but her devotion to corn stranded her between pragmatic scientists helping Iowans grow more bushels and pure geneticists who refused to fuss with unruly corn DNA.

  At last, McClintock secured a job in 1941 at rustic Cold Spring Harbor Laboratory, thirty miles east of Manhattan. Unlike before, she had no students to distract her, and she employed just one assistant—who got a shotgun, and instructions to keep the damn crows off her corn. And although isolated out there with her maize, she was happily isolated. Her few friends always described her as a scientific mystic, constantly chasing the insight that would dissolve the complexity of genetics into unity. “She believed in the great inner lightbulb,” one friend remarked. At Cold Spring she had time and space to meditate, and settled into the most productive decade of her career, right through 1951.

  Her research actually culminated in March 1950, when a colleague received a letter from McClintock. It ran ten single-spaced pages, but whole paragraphs were scribbled out and scribbled over—not to mention other fervid annotations, connected by arrows and climbing like kudzu up and down the margins. It’s the kind of letter you’d think about getting tested for anthrax nowadays, and it described a theory that sounded nutty, too. Morgan had established genes as stationary pearls on a chromosomal necklace. McClintock insisted she’d seen the pearls move—jumping from chromosome to chromosome and burrowing in.

  Moreover, these jumping genes somehow affected the color of kernels. McClintock worked with Indian corn, the kind speckled with red and blue and found on harvest floats in parades. She’d seen the jumping genes attack the arms of chromosomes inside these kernels, snapping them and leaving the ends dangling like a compound fracture. Whenever this happened, the kernels stopped producing pigment. Later, though, when the jumping gene got restless and randomly leaped somewhere else, the broken arm healed, and pigment production started up again. Amid her scribbling, McClintock suggested that the break had disrupted the gene for making the pigments. Indeed, this off/on pattern seemed to explain the randomly colored stripes and swirls of her kernels.

  In other words, jumping genes controlled pigment production; McClintock actually called them “controlling elements.” (Today they’re called transposons or, more generally, mobile DNA.) And like Margulis, McClintock parlayed her fascinating find into a more ambitious theory. Perhaps the knottiest biological question of the 1940s was why cells didn’t all look alike: skin and liver and brain cells contain the same DNA, after all, so why didn’t they act the same? Previous biologists argued that something in the cell’s cytoplasm regulated genes, something external to the nucleus. McClintock had won evidence that chromosomes regulated themselves from within the nucleus—and that this control involved turning genes on or off at the right moments.

  In fact, (as McClintock suspected) the ability to turn genes off and on was a crucial step in life’s history. After Margulis’s complex cells emerged, life once again stalled for over a billion years. Then, around 550 million years ago, huge numbers of multicellular creatures burst into existence. The first beings probably were multicellular by mistake, sticky cells that couldn’t free themselves. But over time, by precisely controlling which genes functioned at which moments in which stuck-together cells, the cells could begin to specialize—the hallmark of higher life. Now McClintock thought she had insight into how this profound change came about.

  McClintock organized her manic letter into a proper talk, which she delivered at Cold Spring in June 1951. Buoyed by hope, she spoke for over two hours that day, reading thirty-five single-spaced pages. She might have forgiven audience members for nodding off, but to her dismay, she found them merely baffled. It wasn’t so much her facts. Scientists knew her reputation, so when she insisted she’d seen genes jump about like fleas, most accepted she had. It was her theory about genetic control that bothered them. Basically, the insertions and jumps seemed too random. This randomness might well explain blue versus red kernels, they granted, but how could jumping genes control all development in multicellular creatures? You can’t build a baby or a beanstalk with genes flickering on and off haphazardly. McClintock didn’t have good answers, and as the hard questions continued, consensus hardened against her. Her revolutionary idea about controlling elements got downgraded* into another queer property of maize.

  Barbara McClintock discovered “jumping genes,” but when other scientists questioned her conclusions about them, she became a scientific hermit, crushed and crestfallen. Inset: McClintock’s beloved maize and microscope. (National Institutes of Health, and Smithsonian Institution, National Museum of American History)

  This demotion hurt McClintock badly. Decades after the talk, she still smoldered about colleagues supposedly sniggering at her, or firing off accusations—You dare question the stationary-gene dogma? There’s little evidence people actually laughed or boiled in rage; again, most accepted jumping genes, just not her theory of control. But McClintock warped the memory into a conspiracy against her. Jumping genes and genetic control had become so interwoven in her heart and mind that attacking one meant attacking both, and attacking her. Crushed, and lacking a brawling disposition, she withdrew from science.*

  So began the hermit phase. For three decades, McClintock continued studying maize, often dozing on a cot in her office at night. But she stopped attending conferences and cut off communication with fellow scientists. After finishing experiments, she usually typed up her results as if to submit them to a journal, then filed the paper away without sending it. If her peers dismissed her, she would hurt them back by ignoring them. And in her (now-depressive) solitude, her mystic side emerged fully. She indulged in speculation about ESP, UFOs, and poltergeists, and studied methods of psychically controlling her reflexes. (When visiting the dentist, she told him not to bother with Novocain, as she could lock out pain with her mind.) All the while, she grew maize and squashed slides and wrote up papers that went as unread as Emily Dickinson’s poems in her day. She was her own sad scientific community.

  Meanwhile something funny was afoot in the larger scientific community, a change a
lmost too subtle to notice at first. The molecular biologists whom McClintock was ignoring began spotting mobile DNA in microbes in the late 1960s. And far from this DNA being a mere novelty, the jumping genes dictated things like whether microbes developed drug resistance. Scientists also found evidence that infectious viruses could (just like mobile DNA) insert genetic material into chromosomes and lurk there permanently. Both were huge medical concerns. Mobile DNA has become vital, too, in tracking evolutionary relationships among species. That’s because if you compare a few species, and just two of them have the same transposon burrowed into their DNA at the same point among billions of bases, then those two species almost certainly shared an ancestor recently. More to the point, they shared that ancestor more recently than either shared an ancestor with a third species that lacks the transposon; far too many bases exist for that insertion to have happened twice independently. What look like DNA marginalia, then, actually reveal life’s hidden recorded history, and for this and other reasons, McClintock’s work suddenly seemed less cute, more profound. As a result her reputation stopped sinking, then rose, year by year. Around 1980 something tipped, and a popular biography of the now-wrinkled McClintock, A Feeling for the Organism, appeared in July 1983, making her a minor celebrity. The momentum bucked out of control after that, and unthinkably, just as her own work had done for Morgan a half century before, the adulation propelled McClintock to a Nobel Prize that October.

  The hermit had been fairy-tale transformed. She became a latter-day Gregor Mendel, a genius discarded and forgotten—only McClintock lived long enough to see her vindication. Her life soon became a rallying point for feminists and fodder for didactic children’s books on never compromising your dreams. That McClintock hated the publicity from the Nobel—it interrupted her research and set reporters prowling about her door—mattered little to fans. And even scientifically, winning the Nobel panged her. The committee had honored her “discovery of mobile genetic elements,” which was true enough. But in 1951 McClintock had imagined she’d unlocked how genes control other genes and control development in multicellular creatures. Instead scientists honored her, essentially, for her microscope skills—for spotting minnows of DNA darting around. For these reasons, McClintock grew increasingly weary of life post-Nobel, even a little morbid: in her late eighties, she started telling friends she’d surely die at age ninety. Months after her ninetieth birthday party, at James Watson’s home, in June 1992, she did indeed pass, cementing her reputation as someone who envisioned things others couldn’t.

  In the end, McClintock’s life’s work remained unfulfilled. She did discover jumping genes and vastly expanded our understanding of corn genetics. (One jumping gene, hopscotch, seems in fact to have transformed the scrawny wild ancestor of corn into a lush, domesticatable crop in the first place.) More generally McClintock helped establish that chromosomes regulate themselves internally and that on/off patterns of DNA determine a cell’s fate. Both ideas remain crucial tenets of genetics. But despite her fondest hopes, jumping genes don’t control development or turn genes on and off to the extent she imagined; cells do these things in other ways. In fact it took other scientists many years to explain how DNA accomplishes those tasks—to explain how powerful but isolated cells pulled themselves together long ago and started building truly complex creatures, even creatures as complex as Miriam Michael Stimson, Lynn Margulis, and Barbara McClintock.

  6

  The Survivors, the Livers

  What’s Our Most Ancient and Important DNA?

  Generations of schoolchildren have learned all about the ruinous amounts of money that European merchants and monarchs spent during colonial days searching for the Northwest Passage—a sailing route to cut horizontally through North America to the spices, porcelain, and tea of Indonesia, India, and Cathay (China). It’s less well known that earlier generations of explorers had hunted just as hard for, and believed with no less delusional determination in, a northeast passage that looped over the frosty top of Russia.

  One explorer seeking the northeast passage—Dutchman Willem Barentsz, a navigator and cartographer from the coastal lowlands who was known in English annals as Barents, Barentz, Barentson, and Barentzoon—made his first voyage in 1594 into what’s known today as the Barents Sea above Norway. While undertaken for mercenary reasons, voyages like Barentsz’s also benefited scientists. Scientific naturalists, while alarmed by the occasional monster that turned up in some savage land, could begin to chart how flora and fauna differ across the globe—work that was a kind of forerunner of our common-descent, common-DNA biology today. Geographers also got much-needed help. Many geographers at the time believed that because of the constant summer sun at high latitudes, polar ice caps melted above a certain point, rendering the North Pole a sunny paradise. And nearly all maps portrayed the pole itself as a monolith of black magnetic rock, which explained why the pole tugged on compasses. In his sally into the Barents Sea, Barentsz aimed to discover if Novaya Zemlya, land north of Siberia, was a promontory of yet another undiscovered continent or merely an island that could be sailed around. He outfitted three ships, Mercury, Swan, and another Mercury, and set out in June 1594.

  A few months later, Barentsz and his Mercury crew broke with the other ships and began exploring the coast of Novaya Zemlya. In doing so, they made one of the more daring runs in exploration history. For weeks, Mercury dodged and ducked a veritable Spanish armada of ice floes, foiling disaster for 1,500 miles. At last Barentsz’s men grew frazzled enough to beg to turn back. Barentsz relented, having proved he could navigate the Arctic Sea, and he returned to Holland certain he’d discovered an easy passage to Asia.

  Easy, if he avoided monsters. The discovery of the New World and the continued exploration of Africa and Asia had turned up thousands upon thousands of never-dreamed-of plants and animals—and provoked just as many wild tales about beasts that sailors swore they’d seen. For their part, cartographers channeled their inner Hieronymus Bosch and spiced up empty seas and steppes on their maps with wild scenes: blood-red krakens splintering ships, giant otters cannibalizing each other, dragons chewing greedily on rats, trees braining bears with macelike branches, not to mention the ever-popular topless mermaid. One important chart of the era, from 1544, shows a rather contemplative Cyclops sitting on the western crook of Africa. Its cartographer, Sebastian Münster, later released an influential compendium of maps interleaved with essays on griffins and avaricious ants that mined gold. Münster also held forth on humanoid-looking beasts around the globe, including the Blemmyae, humans whose faces appeared in their chests; the Cynocephali, people with canine faces; and the Sciopods, grotesque land mermaids with one gargantuan foot, which they used to shade themselves on sunny days by lying down and raising it over their heads. Some of these brutes merely personified (or animalified) ancient fears and superstitions. But amid the farrago of plausible myth and fantastical facts, naturalists could barely keep up.

  Monsters of all stripes proved wildly popular on early maps and filled in blank expanses of land and sea for centuries. (Detail from the 1539 Carta Marina, a map of Scandinavia, by Olaus Magnus)

  Even the most scientific naturalist during the age of exploration, Carl von Linné, d.b.a. Linnaeus, speculated on monsters. Linnaeus’s Systema Naturae set forth the binomial system for naming species that we still use today, inspiring the likes of Homo sapiens and Tyrannosaurus rex. The book also defined a class of animals called “paradoxa,” which included dragons, phoenixes, satyrs, unicorns, geese that sprouted from trees, Heracles’s nemesis the Hydra, and remarkable tadpoles that not only got smaller as they aged, but metamorphosed into fish. We might laugh today, but in the last case at least, the joke’s on us: shrinking tadpoles do exist, although Pseudis paradoxa shrink into regular old frogs, not fish. What’s more, modern genetic research reveals a legitimate basis for some of Linnaeus’s and Münster’s legends.

  A few key genes in every embryo play cartographer for other genes and map out our bodies
with GPS precision, front to back, left to right, and top to bottom. Insects, fish, mammals, reptiles, and all other animals share many of these genes, especially a subset called hox genes. The ubiquity of hox in the animal kingdom explains why animals worldwide have the same basic body plan: a cylindrical trunk with a head at one end, an anus at the other, and various appendages sprouting in between. (The Blemmyae, with faces low enough to lick their navels, would be unlikely for this reason alone.)

  Unusually for genes, hox remain tightly linked after hundreds of millions of years of evolution, almost always appearing together along continuous stretches of DNA. (Invertebrates have one stretch of around ten genes, vertebrates four stretches of basically the same ones.) Even more unusually, each hox’s position along that stretch corresponds closely to its assignment in the body. The first hox designs the top of the head. The next hox designs something slightly lower down. The third hox something slightly lower, and so on, until the final hox designs our nether regions. Why nature requires this top-to-bottom spatial mapping in hox genes isn’t known, but again, all animals exhibit this trait.

  Scientists refer to DNA that appears in the same basic form in many, many species as highly “conserved” because creatures remain very careful, very conservative, about changing it. (Some hox and hox-like genes are so conserved that scientists can rip them out of chickens, mice, and flies and swap them between species, and the genes more or less function the same.) As you might suspect, being highly conserved correlates strongly with the importance of the DNA in question. And it’s easy to see, literally see, why creatures don’t mess with their highly conserved hox genes all that often. Delete one of these genes, and animals can develop multiple jaws. Mutate others and wings disappear, or extra sets of eyes appear in awful places, bulging out on the legs or staring from the ends of antennae. Still other mutations cause genitals or legs to sprout on the head, or cause jaws or antennae to grow in the crotchal region. And these are the lucky mutants; most creatures that gamble with hox and related genes don’t live to speak of it.