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

by Sam Kean

  Genes like hox don’t build animals as much as they instruct other genes on how to build animals: each one regulates dozens of underlings. However important, though, these genes can’t control every aspect of development. In particular, they depend on nutrients like vitamin A.

  Despite the singular name, vitamin A is actually a few related molecules that we non-biochemists lump together for convenience. These various vitamins A are among the most widespread nutrients in nature. Plants store vitamin A as beta carotene, which gives carrots their distinct color. Animals store vitamin A in our livers, and our bodies convert freely between various forms, which we use in a byzantine array of biochemical processes—to keep eyesight sharp and sperm potent, to boost mitochondria production and euthanize old cells. For these reasons, a lack of vitamin A in the diet is a major health concern worldwide. One of the first genetically enhanced foods created by scientists was so-called golden rice, a cheap source of vitamin A with grains tinted by beta carotene.

  Vitamin A interacts with hox and related genes to build the fetal brain, lungs, eyes, heart, limbs, and just about every other organ. In fact, vitamin A is so important that cells build special drawbridges in their membranes to let vitamin A, and only vitamin A, through. Once inside a cell, vitamin A binds to special helper molecules, and the resulting complex binds directly to the double helix of DNA, turning hox and other genes on. While most signaling chemicals get repulsed at the cell wall and have to shout their instructions through small keyholes, vitamin A gets special treatment, and the hox build very little in a baby without a nod from this master nutrient.

  But be warned: before you dash to the health store for megadoses of vitamin A for a special pregnant someone, you should know that too much vitamin A can cause substantial birth defects. In fact the body tightly caps its vitamin A concentration, and even has a few genes (like the awkwardly initialed tgif gene) that exist largely to degrade vitamin A if its concentration creeps too high. That’s partly because high levels of vitamin A in embryos can interfere with the vital, but even more ridiculously named, sonic hedgehog gene.

  (Yes, it’s named for the video game character. A graduate student—one of those wacky fruit fly guys—discovered it in the early 1990s and classified it within a group of genes that, when mutated, cause Drosophila to grow spiky quills all over, like hedgehogs. Scientists had already discovered multiple “hedgehog” genes and named them after real hedgehog species, like the Indian hedgehog, moonrat hedgehog, and desert hedgehog. Robert Riddle thought naming his gene after the speedy Sega hero would be funny. By happenstance, sonic proved one of the most important genes in the animal repertoire, and the frivolity has not worn well. Flaws can lead to lethal cancers or heartbreaking birth defects, and scientists cringe when they have to explain to some poor family that sonic hedgehog will kill a loved one. As one biologist told the New York Times about such names, “It’s a cute name when you have stupid flies and you call [a gene] turnip. When it’s linked to development in humans, it’s not so cute anymore.”)

  Just as hox genes control our body’s top-to-bottom pattern, shh—as scientists who detest the name refer to sonic hedgehog—helps control the body’s left-right symmetry. Shh does so by setting up a GPS gradient. When we’re still a ball of protoplasm, the incipient spinal column that forms our midline starts to secrete the protein sonic produces. Nearby cells absorb lots of it, faraway cells much less. Based on how much protein they absorb, cells “know” exactly where they are in relation to the midline, and therefore know what type of cell they should become.

  But if there’s too much vitamin A around (or if shh fails for a different reason), the gradient doesn’t get set up properly. Cells can’t figure out their longitude in relation to the midline, and organs start to grow in abnormal, even monstrous ways. In severe cases, the brain doesn’t divide into right and left halves; it ends up as one big, undifferentiated blob. The same can happen with the lower limbs: if exposed to too much vitamin A, they fuse together, leading to sirenomelia, or mermaid syndrome. Both fused brains and fused legs are fatal (in the latter case because holes for the anus and bladder don’t develop). But the most distressing violations of symmetry appear on the face. Chickens with too much sonic have faces with extra-wide midlines, sometimes so wide that two beaks form. (Other animals get two noses.) Too little sonic can produce noses with a single giant nostril, or prevent noses from growing at all. In some severe cases, noses appear in the wrong spot, like on the forehead. Perhaps most distressing of all, with too little sonic, the two eyes don’t start growing where they should, an inch or so to the left and right of the facial midline. Both eyes end up on the midline, producing the very Cyclops* that cartographers seemed so silly for including on their maps.

  Linnaeus never included Cyclops in his classification scheme, largely because he came to doubt the existence of monsters. He dropped the category of paradoxa from later editions of Systema Naturae. But in one case Linnaeus might have been too cynical in dismissing the stories he heard. Linnaeus named the genus that bears reside in, Ursus, and he personally named the brown bear Ursus arctos, so he knew bears could live in extreme northern climates. Yet he never discussed the existence of polar bears, perhaps because the anecdotes that would have trickled in to him seemed dubious. Who could credit, after all, barroom tales about a ghost-white bear that stalked men across the ice and tore their heads off for sport? Especially when—and people swore this happened, too—if they killed and ate the white bear, it would extract beyond-the-grave revenge by causing their skin to peel off? But such things did happen to Barentsz’s men, a horror story that winds its way back and around to the same vitamin A that can produce Cyclopes and mermaids.

  Spurred on by the “most exaggerated hopes” of Maurice of Nassau,* a prince of Holland, lords in four Dutch cities filled seven ships with linens, cloths, and tapestries and sent Barentsz back out for Asia in 1595. Haggling delayed the departure until midsummer, and once asea, the captains of the vessels overruled Barentsz (who was merely the navigator) and took a more southerly course than he wished. They did so partly because Barentsz’s northerly route seemed mad, and partly because, beyond reaching China, the Dutch seamen were fired by rumors of a remote island whose shores were studded with diamonds. Sure enough, the crew found the island and landed straightaway.

  Sailors had been stuffing their pockets with the transparent gems for a number of minutes when, as an olde English account had it, “a great leane white beare came sodainly stealing out” and wrapped his paw around one sailor’s neck. Thinking a hirsute sailor had him in a half nelson, he cried out, “Who is that pulles me so by the necke?” His companions, eyes glued to the ground for gems, looked up and just about messed themselves. The polar bear, “falling upon the man, bit his head in sunder, and suckt out his blood.”

  This encounter opened a centuries-long war between explorers and this “cruell, fierce, and rauenous beast.” Polar bears certainly deserved their reputations as mean SOBs. They picked off and devoured any stragglers wherever sailors landed, and they withstood staggering amounts of punishment. Sailors could bury an ax in a bear’s back or pump six bullets into its flank—and often, in its rampage, this just made the bear madder. Then again, polar bears had plenty of grievances, too. As one historian notes, “Early explorers seemed to regard it as their duty to kill polar bears,” and they piled up carcasses like buffalo hunters later would on the Great Plains. Some explorers deliberately maimed bears to keep as pets and paraded them around in rope nooses. One such bear, hauled aboard a small ship, snapped free from its restraints and, after slapping the sailors about, mutinied and took over the ship. In the bear’s fury, though, its noose got tangled in the rudder, and it exhausted itself trying to get free. The brave men retook the ship and butchered the bear.

  During the encounter with Barentsz’s crew, the bear managed to murder a second sailor, and probably would have kept hunting had reinforcements not arrived from the main ship. A sharpshooter put a bullet clean betw
een the bear’s eyes, but the bear shook it off and refused to stop snacking. Other men charged and attacked with swords, but their blades snapped on its head and hide. Finally someone clubbed the beast in the snout and stunned it, enabling another person to slit its throat ear to ear. By this time both sailors had expired, of course, and the rescue squad could do nothing but skin the bear and abandon the corpses.

  The rest of the voyage didn’t turn out much better for Barentsz’s crew. The ships had left too late in the season, and huge floating mines of ice began to threaten their hulls from all sides. The threat swelled each day, and by September, some sailors felt desperate enough to mutiny. Five were hanged. Eventually even Barentsz wilted, fearing the clumsy merchant ships would be stranded in ice. All seven ships returned to port with nothing more than the cargo they’d set out with, and everyone involved lost his frilly shirt. Even the supposed diamonds turned out to be worthless, crumbling glass.

  The voyage would have crippled the confidence of a humble man. All Barentsz learned was not to trust superiors. He’d wanted to sail farther north the whole time, so in 1596 he scraped together funds for two more ships and reembarked. Things started smoothly, but once again, Barentsz’s ship parted ways with its more prudent companion, helmed by one Captain Rijp. And this time Barentsz pushed too far. He reached the northern tip of Novaya Zemlya and rounded it at last, but as soon as he did so, an unseasonable freeze swept down from the Arctic. The cold stalked his ship southward along the coastline, and each day it became harder to shoulder out room between the floes. Pretty soon Barentsz found himself checkmated, marooned on a continent of ice.

  Abandoning their floating coffin—the men could no doubt hear the ice expanding and splintering the ship beneath their feet—the crew staggered ashore to a peninsula on Novaya Zemlya to seek shelter. In their one piece of good luck, they discovered on this treeless island a cache of bleached-white driftwood logs. Naturally the ship’s carpenter up and died immediately, but with that wood and a few timbers salvaged from their ship, the dozen crewmen built a log cabin, about eight yards by twelve yards, complete with pine shingles, a porch, and front stairs. With more hope than irony, they called it Het Behouden Huys, the Saved House, and settled down to a grim winter.

  Cold was the omnipresent danger, but the Arctic had plenty of other minions to harass the men. In November the sun disappeared for three months, and they grew stir-crazy in their dark, fetid cabin. Perversely, fires threatened them too: the crew almost suffocated from carbon monoxide poisoning one night because of poor ventilation. They managed to shoot some white foxes for fur and meat, but the critters constantly nipped at their food supplies. Even laundry became a black comedy. The men had to stick their clothes almost into their fires to get enough heat to dry them. But the garments could be singed and smoking on one side, and the far side would still be brittle with ice.

  For sheer day-to-day terror, however, nothing matched the run-ins with polar bears. One of Barentsz’s men, Garrit de Veer, recorded in his diary of the voyage that the bears practically laid siege to Het Behouden Huys, raiding with military precision the barrels of beef, bacon, ham, and fish stacked outside. One bear, smelling a meal on the hearth one night, crept up with such stealth that it had padded up the back stairs and crossed the back door’s threshold before anyone noticed. Only a lucky musket shot (which passed through the bear and startled it) prevented a massacre in the tiny quarters.

  Fed up, half insane, lusty for revenge, the sailors charged outdoors and followed the blood in the snow until they tracked down and killed the invader. When two more bears attacked over the next two days, the sailors again cut them down. Suddenly in high spirits and hungry for fresh meat, the men decided to feast on the bears, stuffing themselves with anything edible. They gnawed the cartilage off bones and sucked the marrow out, and cooked up all the fleshy victuals—the heart, kidneys, brain, and, most succulent of all, the liver. And with that meal, in a godforsaken cabin at eighty degrees north latitude, European explorers first learned a hard lesson about genetics—a lesson other stubborn Arctic explorers would have to keep learning over and over, a lesson scientists would not understand fully for centuries. Because while polar bear liver may look the same purplish red as any mammal’s liver and smell of the same raw ripeness and jiggle the same way on the tines of a fork, there’s one big difference: on the molecular level, polar bear liver is supersaturated with vitamin A.

  Scenes from Barentsz’s doomed voyage over the frosty top of Russia. Clockwise from top left: encounters with polar bears; the ship crushed in ice; the hut where the crew endured a grim winter in the 1590s. (Gerrit de Veer, The Three Voyages of William Barents to the Arctic Regions)

  Understanding why that’s so awful requires taking a closer look at certain genes, genes that help immature cells in our bodies transform into specialized skin or liver or brain cells or whatever. This was part of the process Barbara McClintock longed to comprehend, but the scientific debate actually predated her by decades.

  In the late 1800s, two camps emerged to explain cell specialization, one led by German biologist August Weismann.* Weismann studied zygotes, the fused product of a sperm and egg that formed an animal’s first cell. He argued that this first cell obviously contained a complete set of molecular instructions, but that each time the zygote and its daughter cells divided, the cells lost half of those instructions. When cells lost the instructions for all but one type of cell, that’s what they became. In contrast, other scientists maintained that cells kept the full set of instructions after each division, but ignored most of the instructions after a certain age. German biologist Hans Spemann decided the issue in 1902 with a salamander zygote. He centered one of these large, soft zygotes in his microscopic crosshairs, waited until it divided into two, then looped a blond strand of his infant daughter Margrette’s hair around the boundary between them. (Why Spemann used his daughter’s hair isn’t clear, since he wasn’t bald. Probably the baby’s hair was finer.) When he tightened this noose, the two cells split, and Spemann pulled them into different dishes, to develop separately. Weismann would have predicted two deformed half salamanders. But both of Spemann’s cells grew into full, healthy adults. In fact, they were genetically identical, which means Spemann had effectively cloned them—in 1902. Scientists had rediscovered Mendel not long before, and Spemann’s work implied that cells must retain instructions but turn genes on and off.

  Still, neither Spemann nor McClintock nor anyone else could explain how cells turned genes off, the mechanism. That took decades’ more work. And it turns out that although cells don’t lose genetic information per se, cells do lose access to this information, which amounts to the same thing. We’ve already seen that DNA must perform incredible acrobatics to fit its entire serpentine length into a tiny cell nucleus. To avoid forming knots during this process, DNA generally wraps itself like a yo-yo string around spools of protein called histones, which then get stacked together and buried inside the nucleus. (Histones were some of the proteins that scientists detected in chromosomes early on, and assumed controlled heredity instead of DNA.) In addition to keeping DNA tangle free, histone spooling prevents cellular machinery from getting at DNA to make RNA, effectively shutting the DNA off. Cells control spooling with chemicals called acetyls. Tacking an acetyl (COCH 3) onto a histone unwinds DNA; removing the acetyl flicks the wrist and coils DNA back up.

  Cells also bar access to DNA by altering DNA itself, with molecular pushpins called methyl groups (CH 3). Methyls stick best to cytosine, the C in the genetic alphabet, and while methyls don’t take up much space—carbon is small, and hydrogen is the smallest element on the periodic table—even that small bump can prevent other molecules from locking onto DNA and turning a gene on. In other words, adding methyl groups mutes genes.

  Each of the two hundred types of cells in our bodies has a unique pattern of coiled and methylated DNA, patterns established during our embryonic days. Cells destined to become skin cells must turn off all the genes tha
t produce liver enzymes or neurotransmitters, and something reciprocal happens for everything else. These cells not only remember their pattern for the rest of their lives, they pass on the pattern each time they divide as adult cells. Whenever you hear scientists talking about turning genes on or off, methyls and acetyls are often the culprit. Methyl groups in particular are so important that some scientists have proposed adding a fifth official letter to the DNAlphabet*—A, C, G, T, and now mC, for methylated cytosine.

  But for additional and sometimes finer control of DNA, cells turn to “transcription factors” like vitamin A. Vitamin A and other transcription factors bind to DNA and recruit other molecules to start transcribing it. Most important for our purposes, vitamin A stimulates growth and helps convert immature cells into full-fledged bone or muscle or whatever at a fast clip. Vitamin A is especially potent in the various layers of skin. In adults, for instance, vitamin A forces certain skin cells to crawl upward from inside the body to the surface, where they die and become the protective outer layer of skin. High doses of vitamin A can also damage skin through “programmed cell death.” This genetic program, a sort of forced suicide, helps the body eliminate sickly cells, so it’s not always bad. But for unknown reasons, vitamin A also seems to hijack the system in certain skin cells—as Barentsz’s men discovered the hard way.

  After the crew tucked into their polar bear stew, rich with burgundy liver chunks, they became more ill than they ever had in their lives. It was a sweaty, fervid, dizzying, bowels-in-a-vice sickness, a real biblical bitch of a plague. In his delirium, the diarist Garrit de Veer remembered the female bear he’d helped butcher, and moaned, “Her death did vs more hurt than her life.” Even more distressing, a few days later de Veer realized that many men’s skin had begun to peel near their lips or mouths, whatever body parts had touched the liver. De Veer noted with panic that three men fell especially “sicke,” and “we verily thought that we should haue lost them, for all their skin came of[f] from the foote to the head.”