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

by Sam Kean

  Only in the mid–twentieth century did scientists determine why polar bear livers contain such astronomical amounts of vitamin A. Polar bears survive mostly by preying on ringed and bearded seals, and these seals raise their young in about the most demanding environment possible, with the 35°F Arctic seas wicking away their body heat relentlessly. Vitamin A enables the seals to survive in this cold: it works like a growth hormone, stimulating cells and allowing seal pups to add thick layers of skin and blubber, and do so quickly. To this end, seal mothers store up whole crates of vitamin A in their livers and draw on this store the whole time they’re nursing, to make sure pups ingest enough.

  Polar bears also need lots of vitamin A to pack on blubber. But even more important, their bodies tolerate toxic levels of vitamin A because they couldn’t eat seals—about the only food source in the Arctic—otherwise. One law of ecology says that poisons accumulate as you move up a food chain, and carnivores at the top ingest the most concentrated doses. This is true of any toxin or any nutrient that becomes toxic at high levels. But unlike many other nutrients, vitamin A doesn’t dissolve in water, so when a king predator overdoses, it can’t expel the excess through urine. Polar bears either have to deal with all the vitamin A they swallow, or starve. Polar bears adapted by turning their livers into high-tech biohazard containment facilities, to filter vitamin A and keep it away from the rest of the body. (And even with those livers, polar bears have to be careful about intake. They can dine on animals lower on the food chain, with lesser concentrations. But some biologists have wryly noted that if polar bears cannibalized their own livers, they would almost certainly croak.)

  Polar bears began evolving their impressive vitamin A–fighting capabilities around 150,000 years ago, when small groups of Alaskan brown bears split off and migrated north to the ice caps. But scientists always suspected that the important genetic changes that made polar bears polar bears happened almost right away, instead of gradually over that span. Their reasoning was this. After any two groups of animals split geographically, they begin to acquire different DNA mutations. As the mutations accumulate, the groups develop into different species with different bodies, metabolisms, and behaviors. But not all DNA changes at the same rate in a population. Highly conserved genes like hox change grudgingly slowly, at geological paces. Changes in other genes can spread quickly, especially if creatures face environmental stress. For instance, when those brown bears wandered onto the bleak ice sheets atop the Arctic Circle, any beneficial mutations to fight the cold—say, the ability to digest vitamin A–rich seals—would have given some of those bears a substantial boost, and allowed them to have more cubs and take better care of them. And the greater the environmental pressure, the faster such genes can and will spread through a population.

  Another way to put this is that DNA clocks—which look at the number and rate of mutations in DNA—tick at different speeds in different parts of the genome. So scientists have to be careful when comparing two species’ DNA and dating how long ago they split. If scientists don’t take conserved genes or accelerated changes into account, their estimates can be wildly off. With these caveats in mind, scientists determined in 2010 that polar bears had armed themselves with enough cold-weather defenses to become a separate species in as few as twenty thousand years after wandering away from ancestral brown bears—an evolutionary wink.

  As we’ll see later, humans are Johnny-come-latelies to the meat-eating scene, so it’s not surprising that we lack the polar bear’s defenses—or that when we cheat up the food chain and eat polar bear livers, we suffer. Different people have different genetic susceptibility to vitamin A poisoning (called hypervitaminosis A), but as little as one ounce of polar bear liver can kill an adult human, and in a ghastly way.

  Our bodies metabolize vitamin A to produce retinol, which special enzymes should then break down further. (These enzymes also break down the most common poison we humans ingest, the alcohol in beers, rums, wines, whiskeys, and other booze.) But polar bear livers overwhelm our poor enzymes with vitamin A, and before they can break it all down, free retinol begins circulating in the blood. That’s bad. Cells are surrounded by oil-based membranes, and retinol acts as a detergent and breaks the membranes down. The guts of cells start leaking out incontinently, and inside the skull, this translates to a buildup of fluids that causes headaches, fogginess, and irritability. Retinol damages other tissues as well (it can even crimp straight hair, turning it kinky), but again the skin really suffers. Vitamin A already flips tons of genetic switches in skin cells, causing some to commit suicide, pushing others to the surface prematurely. The burn of more vitamin A kills whole additional swaths, and pretty soon the skin starts coming off in sheets.

  We hominids have been learning (and relearning) this same hard lesson about eating carnivore livers for an awfully long time. In the 1980s, anthropologists discovered a 1.6-million-year-old Homo erectus skeleton with lesions on his bones characteristic of vitamin A poisoning, from eating that era’s top carnivores. After polar bears arose—and after untold centuries of casualties among their people—Eskimos, Siberians, and other northern tribes (not to mention scavenging birds) learned to shun polar bear livers, but European explorers had no such wisdom when they stormed into the Arctic. Many in fact regarded the prohibition on eating livers as “vulgar prejudice,” a superstition about on par with worshipping trees. As late as 1900 the English explorer Reginald Koettlitz relished the prospect of digging into polar bear liver, but he quickly discovered that there’s sometimes wisdom in taboos. Over a few hours, Koettlitz felt pressure building up inside his skull, until his whole head felt crushed from the inside. Vertigo overtook him, and he vomited repeatedly. Most cruelly, he couldn’t sleep it off; lying down made things worse. Another explorer around that time, Dr. Jens Lindhard, fed polar bear liver to nineteen men under his care as an experiment. All became wretchedly ill, so much so that some showed signs of insanity. Meanwhile other starved explorers learned that not just polar bears and seals have toxically elevated levels of vitamin A: the livers of reindeer, sharks, swordfish, foxes, and Arctic huskies* can make excellent last meals as well.

  For their part, after being blasted by polar bear liver in 1597, Barentsz’s men got wise. As the diarist de Veer had it, after their meal, “there hung a pot still ouer the fire with some of the liuer in it. But the master tooke it and cast it out of the dore, for we had enough of the sawce thereof.”

  The men soon recovered their strength, but their cabin, clothes, and morale continued to disintegrate in the cold. At last, in June, the ice started melting, and they salvaged rowboats from their ship and headed to sea. They could only dart between small icebergs at first, and they took heavy flak from pursuing polar bears. But on June 20, 1597, the polar ice broke, making real sailing possible. Alas, June 20 also marked the last day on earth of the long-ailing Willem Barentsz, who died at age fifty. The loss of their navigator sapped the courage of the remaining twelve crew members, who still had to cross hundreds of miles of ocean in open boats. But they managed to reach northern Russia, where the locals pitied them with food. A month later they washed ashore on the coast of Lapland, where they ran into, of all people, Captain Jan Corneliszoon Rijp, commander of the very ship that Barentsz had ditched the winter before. Overjoyed—he’d assumed them dead—Rijp carried the men home to the Netherlands* in his ship, where they arrived in threadbare clothes and stunning white fox fur hats.

  Their expected heroes’ welcome never materialized. That same day another Dutch convoy returned home as well, laden with spices and delicacies from a voyage to Cathay around the southern horn of Africa. Their journey proved that merchant ships could make that long voyage, and while tales of starvation and survival were thrilling, tales of treasure truly stirred the Dutch people’s hearts. The Dutch crown granted the Dutch East India Company a monopoly on traveling to Asia via Africa, and an epic trade route was born, a mariner’s Silk Road. Barentsz and crew were forgotten.

  Perversely,
the monopoly on the African route to Asia meant that other maritime entrepreneurs could seek their fortunes only via the northeast passage, so forays into the 500,000-square-mile Barents Sea continued. Finally, salivating over a possible double monopoly, the Dutch East India Company sent its own crew—captained by an Englishman, Henry Hudson—north in 1609. Once again, things got fouled up. Hudson and his ship, the Half Moon, crawled north past the tip of Norway as scheduled. But his crew of forty, half of them Dutch, had no doubt heard tales of starvation, exposure, and, God help them, skin peeling off people’s bodies head to toe—and mutinied. They forced Hudson to turn west.

  If that’s what they wanted, Hudson gave it to them, sailing all the way west to North America. He skimmed Nova Scotia and put in at a few places lower down on the Atlantic coast, including a trip up a then-unnamed river, past a skinny swamp island. While disappointed that Hudson had not circled Russia, the Dutch made lemonade by founding a trading colony called New Amsterdam on that isle, Manhattan, within a few years. It’s sometimes said of human beings that our passion for exploration is in our genes. With the founding of New York, this was almost literally the case.

  7

  The Machiavelli Microbe

  How Much Human DNA Is Actually Human?

  A farmer from Long Island arrived with trepidation at the Rockefeller Institute in Manhattan in 1909, a sick chicken tucked under his arm. A seeming plague of cancer had been wiping out chicken coops across the United States that decade, and the farmer’s Plymouth Rock hen had developed a suspicious tumor in its right breast. Nervous about losing his stocks, the farmer turned the hen over to Rockefeller scientist Francis P. Rous, known as Peyton, for a diagnosis. To the farmer’s horror, instead of trying to cure the chicken, Rous slaughtered it to get a look at the tumor and run some experiments. Science, though, will be forever grateful for the pollocide.

  After extracting the tumor, Rous mashed up a few tenths of an ounce, creating a wet paste. He then filtered it through very small porcelain pores, which removed tumor cells from circulation and left behind mostly just the fluid that exists between cells. Among other things, this fluid helps pass nutrients around, but it can also harbor microbes. Rous injected the fluid into another Plymouth Rock’s breast. Soon enough, the second chicken developed a tumor. Rous repeated the experiment with other breeds, like Leghorn fowls, and within six months they developed cancerous masses, about an inch by an inch, too. What was notable, and baffling, about the setup was the filtering step. Since Rous had removed any tumor cells before making the injections, the new tumors couldn’t have sprung from old tumor cells reattaching themselves in new birds. The cancer had to have come from the fluid.

  Though annoyed, the farmer couldn’t have sacrificed his hen to a better candidate to puzzle out the chicken pandemic. Rous, a medical doctor and pathologist, had a strong background with domesticated animals. Rous’s father had fled Virginia just before the Civil War and settled in Texas, where he met Peyton’s mother. The whole family eventually moved back east to Baltimore, and after high school, Rous enrolled at the Johns Hopkins University, where he supported himself in part by writing, for five dollars a pop, a column called “Wild Flowers of the Month” for the Baltimore Sun, about flora in Charm City. Rous gave up the column after entering Johns Hopkins medical school but soon had to suspend his studies. He cut his hand on a tubercular cadaver bone while performing an autopsy, and when he developed tuberculosis himself, school officials ordered a rest cure. But instead of a European-style cure—an actually restful stint in a mountain sanitarium—Rous took a good ol’ American cure and worked as a ranch hand in Texas. Though small and slender, Rous loved ranching and developed a keen interest in farm animals. After recovering, he decided to specialize in microbial biology instead of bedside medicine.

  All the training on the ranch and in his labs, and all the evidence of the chicken case, pointed Rous to one conclusion. The chickens had a virus, and the virus was spreading cancer. But all his training also told Rous the idea was ridiculous—and his colleagues seconded that. Contagious cancer, Dr. Rous? How on earth could a virus cause cancer? Some argued that Rous had misdiagnosed the tumors; perhaps the injections caused an inflammation peculiar to chickens. Rous himself later admitted, “I used to quake in the night for fear that I had made an error.” He did publish his results, but even by the circuitous standards of scientific prose, he barely admitted what he believed at some points: “It is perhaps not too much to say that [the discovery] points to the existence of a new group of entities which cause in chickens neoplasms [tumors] of diverse character.” But Rous was cagey to be circumspect. A contemporary remembered that his papers on the chicken cancers “were met with reactions ranging from indifference to skepticism and outright hostility.”

  Most scientists quietly forgot about Rous’s work over the next few decades, and for good reason. Because even though a few discoveries from that time linked viruses and cancers biologically, other findings kept pushing them apart. Scientists had determined by the 1950s that cancer cells go haywire in part because their genes malfunction. Scientists had also determined that viruses have small caches of their own genetic material. (Some used DNA; others, like Rous’s, used RNA.) Though not technically alive, viruses used that genetic material to hijack cells and make copies of themselves. So viruses and cancer both reproduced uncontrollably, and both used DNA and RNA as common currency—intriguing clues. Meanwhile, however, Francis Crick had published his Central Dogma in 1958, that DNA generates RNA, which generates proteins, in that order. According to this popular understanding of the dogma, RNA viruses like Rous’s couldn’t possibly disrupt or rewrite the DNA of cells: this would run the dogma backward, which wasn’t allowed. So despite the biological overlap, there seemed no way for viral RNA to interface with cancer-causing DNA.

  The matter stood at an impasse—data versus dogma—until a few young scientists in the late 1960s and early 1970s discovered that nature cares little for dogmas. It turns out that certain viruses (HIV is the best-known example) manipulate DNA in heretical ways. Specifically, the viruses can coax an infected cell into reverse-transcribing viral RNA into DNA. Even scarier, they then trick the cell into splicing the newly minted viral DNA back into the cell’s genome. In short, these viruses fuse with a cell. They show no respect for the Maginot Line we’d prefer to draw between “their” DNA and “our” DNA.

  This strategy for infecting cells might seem convoluted: why would an RNA virus like HIV bother converting itself into DNA, especially when the cell has to transcribe that DNA back into RNA later anyway? It seems even more baffling when you consider how resourceful and nimble RNA is compared to DNA. Lone RNA can build rudimentary proteins, whereas lone DNA sort of just sits there. RNA can also build copies of itself by itself, like that M. C. Escher drawing of two hands sketching themselves into existence. For these reasons, most scientists believe that RNA probably predated DNA in the history of life, since early life would have lacked the fancy innards-copying equipment cells have nowadays. (This is called the “RNA world” theory.*)

  Nevertheless, early Earth was rough-and-tumble, and RNA is pretty flimsy compared to DNA. Because it’s merely single-stranded, RNA letters are constantly exposed to assaults. RNA also has an extra oxygen atom on its ringed sugars, which stupidly cannibalizes its own vertebrae and shreds RNA if it grows too long. So to build anything lasting, anything capable of exploring, swimming, growing, fighting, mating—truly living—fragile RNA had to yield to DNA. This transition to a less corruptible medium a few billion years ago was arguably the most important step in life’s history. In a way it resembled the transition in human cultures away from, say, Homer’s oral poetry to mute written work: with a stolid DNA text, you miss the RNA-like versatility, the nuances of voice and gesture; but we wouldn’t even have the Iliad and the Odyssey today without papyrus and ink. DNA lasts.

  And that’s why some viruses convert RNA into DNA after infecting cells: DNA is sturdier, more enduring. Once the
se retro viruses—so named because they run the DNA → RNA → protein dogma backward—weave themselves into a cell’s DNA, the cell will faithfully copy the virus genes so long as they both shall live.

  The discovery of viral DNA manipulation explained Rous’s poor chickens. After the injection, the viruses found their way through the intercellular fluid into the muscle cells. They then ingratiated themselves with the chicken DNA and turned the machinery of each infected muscle cell toward making as many copies of themselves as possible. And it turns out—here’s the key—one great strategy for the viruses to spread like mad was to convince the cells harboring viral DNA to spread like mad, too. The viruses did this by disrupting the genetic governors that prevent cells from dividing rapidly. A runaway tumor (and a lot of dead birds) was the result. Transmissible cancers like this are atypical—most cancers have other genetic causes—but for many animals, virus-borne cancers are significant hazards.

  This new theory of genetic intrusions was certainly unorthodox. (Even Rous doubted aspects of it.) But if anything, scientists of the time actually underestimated the ability of viruses and other microbes to invade DNA. You can’t really attach degrees to the word ubiquitous; like being unique, something either is or isn’t ubiquitous. But indulge me for a moment in marveling over the complete, total, and utter ubiquity of microbes on a microscopic scale. The little buggers have colonized every known living thing—humans have ten times more microorganisms feasting inside us than we do cells—and saturated every possible ecological niche. There’s even a class of viruses that infect only other parasites,* which are scarcely larger than the viruses themselves. For reasons of stability, many of these microbes invade DNA, and they’re often nimble enough about changing or masking their DNA to evade and outflank our bodies’ defenses. (One biologist calculated that HIV alone has swapped more A’s, C’s, G’s, and T’s into and out of its genes in the past few decades than primates have in fifty million years.)