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

by Sam Kean

  Except—what about those hydrogen bonds? It’s been lost after a half century of hosannas, but Watson and Crick’s model rested on an unwarranted, even shaky, assumption. Their bases fit snugly inside the double helix—and fit with proper hydrogen bonds—only if each base had one specific shape, not another. But after Miriam’s work was upended, no one knew what shapes the bases had inside living beings.

  Determined to help this time, Sister Miriam returned to the lab bench. After the acid-ultraviolet fiasco, she explored DNA with light from the opposite side of the spectrum, the infrared. The standard way to probe a substance with infrared light involved blending it with liquid, but DNA bases wouldn’t always mix properly. So Miriam invented a way to mix DNA with a white powder, potassium bromide. To make samples thin enough to study, Miriam’s lab team had to borrow a mold from the nearby Chrysler corporation that would shape the powder into “pills” the diameter of an aspirin, then travel to a local machine shop to stamp the pills, with an industrial press, into discs one millimeter thick. The sight of a cab full of nuns in habit descending on a filthy machine shop tickled the grease monkeys on duty, but Miriam remembered them treating her with gentlemanly politeness. And eventually the air force donated a press to her lab so that she could stamp out discs herself. (She had to hold the press down, students remember, long enough to say two Hail Marys.) Because thin layers of potassium bromide were invisible to infrared, the light tickled only the A’s, C’s, G’s, and T’s as it streamed through. And over the next decade, infrared studies with the discs (along with other work) proved Watson and Crick right: DNA bases had only one natural shape, the one that produced perfect hydrogen bonds. At this point, and only at this point, could scientists say they grasped DNA’s structure.

  Of course, understanding its structure wasn’t the final goal; scientists had more research ahead. But although M2 continued to do outstanding work—in 1953 she lectured at the Sorbonne, the first woman scientist to do so since Madame Curie—and although she lived until 2002, reaching the age of eighty-nine, her scientific ambitions petered out along the way. In the swinging 1960s, she doffed her hooded habit for the last time (and learned how to drive), but despite this minor disobedience, she devoted herself to her order during her last decades and stopped experimenting. She let other scientists, including two other women pioneers, unravel how DNA actually builds complex and beautiful life.*

  The history of science teems with duplicate discoveries. Natural selection, oxygen, Neptune, sunspots—two, three, even four scientists discovered each independently. Historians continue to bicker about why this happens: perhaps each case was a gigantic coincidence; perhaps one presumed discoverer stole ideas; perhaps the discoveries were impossible before circumstances favored them, and inevitable once they did. But no matter what you believe, scientific simultaneity is a fact. Multiple teams almost sussed out the double helix, and in 1963 two teams did discover another important aspect of DNA. One group was using microscopes to map mitochondria, bean-shaped organs that supply energy inside cells. The other group was pureeing mitochondria and sifting through the guts. Both turned up evidence that mitochondria have their own DNA. In trying to burnish his reputation at the end of the 1800s, Friedrich Miescher had defined the nucleus as the exclusive home for DNA; history once again crossed Friedrich Miescher.

  If historical circumstances favor some discoveries, though, science also needs mavericks, those counterclockwise types who see what circumstances blind the rest of us to. Sometimes we even need obnoxious mavericks—because if they’re not pugnacious, their theories never penetrate our attention. Such was the case with Lynn Margulis. Most scientists in the mid-1960s explained the origin of mitochondrial DNA rather dully, arguing that cells must have loaned a bit of DNA out once and never gotten it back. But for two decades, beginning in her Ph.D. thesis in 1965, Margulis pushed the idea that mitochondrial DNA was no mere curiosity. She saw it instead as proof of something bigger, proof that life has more ways of mixing and evolving than conventional biologists ever dreamed.

  Margulis’s theory, endosymbiosis, went like this. We all descended long ago from the first microbes on earth, and all living organisms today share certain genes, on the order of one hundred, as part of that legacy. Soon enough, though, these early microbes began to diverge. Some grew into mammoth blobs, others shrank into specks, and the size difference created opportunities. Most important, some microbes began swallowing and digesting others, while others infected and killed the large and unwary. For either reason, Margulis argued, a large microbe ingested a bug one afternoon long, long ago, and something strange happened: nothing. Either the little Jonah fought off being digested, or his host staved off an internal coup. A standoff followed, and although each one kept fighting, neither could polish the other off. And after untold generations, this initially hostile encounter thawed into a cooperative venture. Gradually the little guy became really good at synthesizing high-octane fuel from oxygen; gradually the whale cell lost its power-producing abilities and specialized instead in providing raw nutrients and shelter. As Adam Smith might have predicted, this division of biolabor benefited each party, and soon neither side could abandon the other without dying. We call the microscopic bugs our mitochondria.

  A nice theory overall—but just that. And unfortunately, when Margulis proposed it, scientists didn’t respond so nicely. Fifteen journals rejected Margulis’s first paper on endosymbiosis, and worse, many scientists outright attacked its speculations. Every time they did, though, she marshaled more evidence and became more pugnacious in emphasizing the independent behavior of mitochondria—that they backstroke about inside cells, that they reproduce on their own schedule, that they have their own cell-like membranes. And their vestigial DNA clinched the case: cells seldom let DNA escape the nucleus to the cellular exurbs, and DNA rarely survives if it tries. We also inherit this DNA differently than chromosome DNA—exclusively from our mothers, since a mother supplies her children with all their mitochondria. Margulis concluded that so-called mtDNA could only have come from once-sovereign cells.

  Her opponents countered (correctly) that mitochondria don’t work alone; they need chromosomal genes to function, so they’re hardly independent. Margulis parried, saying that after three billion years it’s not surprising if many of the genes necessary for independent life have faded, until just the Cheshire Cat grin of the old mitochondrial genome remains today. Her opponents didn’t buy that—absence of evidence and all—but unlike, say, Miescher, who lacked much backbone for defending himself, Margulis kept swinging back. She lectured and wrote widely on her theory and delighted in rattling audiences. (She once opened a talk by asking, “Any real biologists here? Like molecular biologists?” She counted the raised hands and laughed. “Good. You’re going to hate this.”)

  Biologists did hate endosymbiosis, and the spat dragged on and on until new scanning technology in the 1980s revealed that mitochondria store their DNA not in long, linear chromosomes (as animals and plants do) but in hoops, as bacteria do. The thirty-seven tightly packed genes on the hoop built bacteria-like proteins as well, and the A-C-G-T sequence itself looked remarkably bacterial. Working from this evidence, scientists even identified living relatives of mitochondria, such as typhoid bacteria. Similar work established that chloroplasts—greenish specks that manage photosynthesis inside plants—also contain looped DNA. As with mitochondria, Margulis had surmised that chloroplasts evolved when large ancestor microbes swallowed photosynthesizing pond scum, and Stockholm syndrome ensued. Two cases of endosymbiosis were too much for opponents to explain away. Margulis was vindicated, and she crowed.

  In addition to explaining mitochondria, Margulis’s theory has since helped solve a profound mystery of life on earth: why evolution damn near stalled after such a promising beginning. Without the kick start of mitochondria, primitive life might never have developed into higher life, much less intelligent human beings.

  To see how profound the stall was, consider how easily the un
iverse manufactures life. The first organic molecules on earth probably appeared spontaneously near volcanic vents on the ocean floor. Heat energy there could fuse simple carbon-rich molecules into complex amino acids and even vesicles to serve as crude membranes. Earth also likely imported organics from space. Astronomers have discovered naked amino acids floating in interstellar dust clouds, and chemists have calculated that DNA bases like adenine might form in space, too, since adenine is nothing but five simple HCN molecules (cyanide, of all things) squished into a double ring. Or icy comets might have incubated DNA bases. As ice forms, it gets quite xenophobic and squeezes any organic impurities inside it into concentrated bubbles, pressure-cooking the gook and making the formation of complicated molecules more likely. Scientists already suspect that comets filled our seas with water as they bombarded the early earth, and they might well have seeded our oceans with bio-bits.

  From this simmering organic broth, autonomous microorganisms with sophisticated membranes and replaceable moving parts emerged in just a billion years. (Pretty speedy, if you think about it.) And from this common beginning, many distinct species popped up in short order, species with distinct livelihoods and clever ways of carving out a living. After this miracle, however, evolution flatlined: we had many types of truly living creatures, but these microbes didn’t evolve much more for well over a billion years—and might never have.

  What doomed them was energy consumption. Primitive microbes expend 2 percent of their total energy copying and maintaining DNA, but 75 percent of their energy making proteins from DNA. So even if a microbe develops the DNA for an advantageous and evolutionarily advanced trait—like an enclosed nucleus, or a “belly” to digest other microbes, or an apparatus to communicate with peers—actually building the advanced feature pretty much depletes it. Adding two is out of the question. In these circumstances, evolution idles; cells can get only so sophisticated. Cheap mitochondrial power lifted those restrictions. Mitochondria store as much energy per unit size as lightning bolts, and their mobility allowed our ancestors to add many fancy features at once, and grow into multifaceted organisms. In fact, mitochondria allowed cells to expand their DNA repertoire 200,000 times, allowing them not only to invent new genes but to add tons of regulatory DNA, making them far more flexible when using genes. This could never have happened without mitochondria, and we might never have illuminated this evolutionary dark age without Margulis’s theory.

  MtDNA opened up whole new realms of science as well, like genetic archaeology. Because mitochondria reproduce on their own, mtDNA genes are abundant in cells, much more so than chromosome genes. So when scientists go digging around in cavemen or mummies or whatever, they’re often rooting out and examining mtDNA. Scientists can also use mtDNA to trace genealogies with unprecedented accuracy. Sperm carry little more than a nuclear DNA payload, so children inherit all their mitochondria from their mothers’ much roomier eggs. MtDNA therefore gets passed down largely unchanged through female lines for generation after generation, making it ideal to trace maternal ancestry. What’s more, because scientists know how quickly any rare changes do accumulate in a mitochondrial line—one mutation every 3,500 years—they can use mtDNA as a clock: they compare two people’s mtDNA, and the more mutations they find, the more years that have passed since the two people shared a maternal ancestor. In fact, this clock tells us that all seven billion people alive today can trace their maternal lineage to one woman who lived in Africa 170,000 years ago, dubbed “Mitochondrial Eve.” Eve wasn’t the only woman alive then, mind you. She’s simply the oldest matrilineal ancestor* of everyone living today.

  After mitochondria proved so vital to science, Margulis used her momentum and sudden prestige to advance other offbeat ideas. She began arguing that microbes also donated various locomotor devices to animals, like the tails on sperm, even though those structures lack DNA. And beyond cells merely picking up spare parts, she outlined a grander theory in which endosymbiosis drives all evolution, relegating mutations and natural selection to minor roles. According to this theory, mutations alter creatures only modestly. Real change occurs when genes leap from species to species, or when whole genomes merge, fusing wildly different creatures together. Only after these “horizontal” DNA transfers does natural selection begin, merely to edit out any hopeless monsters that emerge. Meanwhile the hopeful monsters, the beneficiaries of mergers, flourish.

  Though Margulis called it revolutionary, in some ways her merger theory just extends a classic debate between biologists who favor (for whatever reasons you want to psychoanalyze) bold leaps and instant species, and biologists who favor conservative adjustments and gradual speciation. The arch-gradualist Darwin saw modest change and common descent as nature’s law, and favored a slow-growing tree of life with no overlapping branches. Margulis fell into the radical camp. She argued that mergers can create honest-to-goodness chimeras—blends of creatures technically no different than mermaids, sphinxes, or centaurs. From this point of view, Darwin’s quaint tree of life must give way to a quick-spun web of life, with interlocking lines and radials.

  However far she strayed into radical ideas, Margulis earned her right to dissent. It’s even a little two-faced to praise someone for holding fast to unconventional scientific ideas sometimes and chastise her for not conforming elsewhere; you can’t necessarily just switch off the iconoclastic part of the mind when convenient. As renowned biologist John Maynard Smith once admitted, “I think [Margulis is] often wrong, but most of the people I know think it’s important to have her around, because she’s wrong in such fruitful ways.” And lest we forget, Margulis was right in her first big idea, stunningly so. Above all, her work reminds us that pretty plants and things with backbones haven’t dominated life’s history. Microbes have, and they’re the evolutionary fodder from which we multicellular creatures rose.

  If Lynn Margulis relished conflict, her older contemporary Barbara McClintock shunned it. McClintock preferred quiet rumination over public confrontation, and her peculiar ideas sprang not from any contrarian streak but from pure flakiness. It’s fitting, then, that McClintock dedicated her life to navigating the oddball genetics of plants like maize. By embracing the eccentricity of maize, McClintock expanded our notions of what DNA can do, and provided vital clues for understanding a second great mystery of our evolutionary past: how DNA builds multicellular creatures from Margulis’s complex but solo cells.

  McClintock’s bio divides into two eras: the fulfilled, pre-1951 scientist, and the bitter, post-1951 hermit. Not that things were all daffodils before 1951. From a very young age McClintock squabbled intensely with her mother, a pianist, mostly because Barbara showed more stubborn interest in science and sports like ice skating than the girlish pastimes her mother always said would improve her dating prospects. Her mother even vetoed Barbara’s dream to (like Hermann Muller and William Friedman before her) study genetics at Cornell, because nice boys didn’t marry brainy gals. Thankfully for science, Barbara’s father, a physician, intervened before the fall 1919 semester and packed his daughter off to upstate New York by train.

  At Cornell, McClintock flourished, becoming the freshmen women’s class president and starring in science classes. Still, her science classmates didn’t always appreciate her sharp tongue, especially her lashings over their microscopy work. In that era, preparing microscope samples—slicing cells like deli ham and mounting their gelatinous guts on multiple glass slides without spilling—was intricate and demanding work. Actually using scopes was tricky, too: identifying what specks were what inside a cell could flummox even a good scientist. But McClintock mastered microscopy early, becoming legitimately world-class by graduation. As a graduate student at Cornell, she then honed a technique—“the squash”—that allowed her to flatten whole cells with her thumb and keep them intact on one slide, making them easier to study. Using the squash, she became the first scientist to identify all ten maize chromosomes. (Which, as anyone who’s ever gone cross-eyed squinting at the spaghet
ti mess of chromosomes inside real cells knows, ain’t easy.)

  Cornell asked McClintock to become a full-time researcher and instructor in 1927, and she began studying how chromosomes interact, with assistance from her best student, Harriet Creighton. Both of these tomboys wore their hair short and often dressed mannishly, in knickers and high socks. People mixed up anecdotes about them, too—like which was it exactly who’d shinnied up a drainpipe one morning after forgetting the keys to her second-story office. Creighton was more outgoing; the reserved McClintock would never have bought a jalopy, as Creighton did, to celebrate the end of World War II and cruise to Mexico. Nonetheless they made a wonderful team, and soon made a seminal discovery. Morgan’s fruit fly boys had demonstrated years before that chromosomes probably crossed arms and swapped tips. But their arguments remained statistical, based on abstract patterns. And while many a microscopist had seen chromosomes entangling, no one could tell if they actually exchanged material. But McClintock and Creighton knew every corn chromosome’s every knob and carbuncle by sight, and they determined that chromosomes did physically exchange segments. They even linked these exchanges to changes in how genes worked, a crucial confirmation. McClintock dawdled in writing up these results, but when Morgan got wind of them, he insisted she publish, posthaste. She did in 1931. Morgan won his Nobel Prize two years later.