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

by Sam Kean

  Nevertheless, despite this and other work, Rous grew suspicious that geneticists were getting ahead of themselves, and he refused to connect the dots that other scientists were eagerly connecting. For example, before he would publish the paper linking genes and DNA, he made the head scientist strike out a sentence suggesting that DNA was as important to cells as amino acids. Indeed, Rous came to reject the very idea that viruses cause cancer by injecting genetic material, as well as the idea that DNA mutations cause cancer at all. Rous believed viruses promoted cancer in other ways, possibly by releasing toxins; and although no one knows why, he struggled to accept that microbes could influence animal genetics quite as much as his work implied.

  Still, Rous never wavered in his conviction that viruses cause tumors somehow, and as his peers unraveled the complicated details of his contagious chicken cancer, they began to appreciate the clarity of his early work all the more. Respect was still grudging in some quarters, and Rous had to endure his much younger son-in-law winning a Nobel Prize for medicine in 1963. But in 1966 the Nobel committee finally vindicated Francis Peyton Rous with a prize of his own. The gap between Rous’s important papers and his Nobel, fifty-five years, is one of the longer in prize history. But the win no doubt proved one of the most satisfying, even if he had just four years to enjoy it before dying in 1970. And after his death, it ceased to matter what Rous himself had believed or rejected; young microbiologists, eager to explore how microbes reprogram life, held him up as an idol, and textbooks today cite his work as a classic case of an idea condemned in its own time and later exonerated by DNA evidence.

  The story of Cat Crossing also ended in a complicated fashion. As the bills piled higher, creditors nearly seized the Wrights’ house. Only donations from cat lovers saved them. Around this time, newspapers also began digging into Jack’s past, and reported that, far from being an innocent animal lover, he’d once been convicted of manslaughter for strangling a stripper. (Her body was found on a roof.) Even after these crises passed, the daily hassles continued for Jack and Donna. One visitor reported that “neither had any vacation, any new clothes, any furniture, or draperies.” If they rose in the night to go to the bathroom, the dozens of cats on their bed would expand like amoebas to fill the warm hollow, leaving no room to crawl back beneath the covers. “Sometimes you think it’ll make you crazy,” Donna once confessed. “We can’t get away… I cry just about every day in the summertime.” Unable to stand the little indignities anymore, Donna eventually moved out. Yet she got drawn back in, unable to walk away from her cats. She returned every dawn to help Jack cope.*

  Despite the near certainty of Toxo exposure and infection, no one knows to what extent (if any) Toxo turned Jack and Donna’s life inside out. But even if they were infected—and even if neurologists could prove that Toxo manipulated them profoundly—it’s hard to censure someone for caring so much for animals. And in a (much, much) larger perspective, the behavior of hoarders might be doing some greater evolutionary good, in the Lynn Margulis sense of mixing up our DNA. Interactions with Toxo and other microbes have certainly influenced our evolution at multiple stages, perhaps profoundly. Retroviruses colonized our genome in waves, and a few scientists argue that it’s not a coincidence that these waves appeared just before mammals began to flourish and just before hominid primates emerged. This finding dovetails with another recent theory that microbes may explain Darwin’s age-old quandary of the origin of new species. One traditional line of demarcation between species is sexual reproduction: if two populations can’t breed and produce viable children, they’re separate species. Usually the reproductive barriers are mechanical (animals don’t “fit”) or biochemical (no viable embryos result). But in one experiment with Wolbachia (the Herod-Tiresias bug), scientists took two populations of infected wasps that couldn’t produce healthy embryos in the wild and gave them antibiotics. This killed the Wolbachia—and suddenly allowed the wasps to reproduce. Wolbachia alone had driven them apart.

  Along these lines, a few scientists have speculated that if HIV ever reached truly epidemic levels and wiped out most people on earth, then the small percentage of people immune to HIV (and they do exist) could evolve into a new human species. Again, it comes down to sexual barriers. These people couldn’t have sex with the nonimmune population (most of us) without killing us off. Any children from the union would have a good chance of dying of HIV, too. And once erected, these sexual and reproductive barriers would slowly but inevitably drive the two populations apart. Even more wildly, HIV, as a retrovirus, could someday insert its DNA into these new humans in a permanent way, joining the genome just as other viruses have. HIV genes would then be copied forever in our descendants, who might have no inkling of the destruction it once wrought.

  Of course, saying that microbes infiltrate our DNA may be nothing but a species-centric bias. Viruses have a haiku-like quality about them, some scientists note, a concentration of genetic material that their hosts lack. Some scientists also credit viruses with creating DNA in the first place (from RNA) billions of years ago, and they argue that viruses still invent most new genes today. In fact the scientists who discovered bornavirus DNA in humans think that, far from the bornavirus forcing this DNA into us primates, our chromosomes stole this DNA instead. Whenever our mobile DNA starts swimming about, it often grabs other scraps of DNA and drags them along to wherever it’s going. Bornavirus replicates only in the nucleus of cells, where our DNA resides, and there’s a good chance that mobile DNA mugged the bornavirus long ago, kidnapped its DNA, and kept it around when it proved useful. Along these lines, I’ve accused Toxo of stealing the dopamine gene from its more sophisticated mammalian hosts. And historical evidence suggests it did. But Toxo also hangs out primarily in the cell nucleus, and there’s no theoretical reason we couldn’t have stolen this gene from it instead.

  It’s hard to decide what’s less flattering: that microbes outsmarted our defenses and inserted, wholly by accident, the fancy genetic tools that mammals needed to make certain evolutionary advances; or that mammals had to shake down little germs and steal their genes instead. And in some cases these truly were advances, leaps that helped make us human. Viruses probably created the mammalian placenta, the interface between mother and child that allows us to give birth to live young and enables us to nurture our young. What’s more, in addition to producing dopamine, Toxo can ramp up or ramp down the activity of hundreds of genes inside human neurons, altering how the brain works. The bornavirus also lives and works between the ears, and some scientists argue that it could be an important source for adding variety to the DNA that forms and runs the brain. This variety is the raw material of evolution, and passing around microbes like the bornavirus from human to human, probably via sex, might well have increased the chances of someone getting beneficial DNA. In fact, most microbes responsible for such boosts likely got passed around via sex. Which means that, if microbes were as important in pushing evolution forward as some scientists suggest, STDs could be responsible in some way for human genius. Descended from apes indeed.

  As the virologist Luis Villarreal has noted (and his thoughts apply to other microbes), “It is our inability to perceive viruses, especially the silent virus, that has limited our understanding of the role they play in all life. Only now, in the era of genomics, can we more clearly see ubiquitous footprints in the genomes of all life.” So perhaps we can finally see too that people who hoard cats aren’t crazy, or at least not merely crazy. They’re part of the fascinating and still-unfolding story of what happens when you mix animal and microbe DNA.

  8

  Love and Atavisms

  What Genes Make Mammals Mammals?

  Given the thousands upon thousands of babies born in and around Tokyo each year, most don’t attract much attention, and in December 2005, after forty weeks and five days of pregnancy, a woman named Mayumi quietly gave birth to a baby girl named Emiko. (I’ve changed the names of family members for privacy’s sake.) Mayumi was twenty-ei
ght, and her blood work and sonograms seemed normal throughout her pregnancy. The delivery and its aftermath were also routine—except that for the couple involved, of course, a first child is never routine. Mayumi and her husband, Hideo, who worked at a petrol station, no doubt felt all the normal fluttering anxieties as the ob-gyn cleared the mucus from Emiko’s mouth and coaxed her into her first cry. The nurses drew blood from Emiko for routine testing, and again, everything came back normal. They clamped and cut Emiko’s umbilical cord, her lifeline to her mother’s placenta, and it dried out eventually, and the little stub blackened and fell off in the normal fashion, leaving her with a belly button. A few days later, Hideo and Mayumi left the hospital in Chiba, a suburb across the bay from Tokyo, with Emiko in their arms. All perfectly normal.

  Thirty-six days after giving birth, Mayumi began bleeding from her vagina. Many women experience vaginal hemorrhages after birth, but three days later, Mayumi also developed a robust fever. With the newborn Emiko to take care of, the couple toughed out Mayumi’s spell at home for a few days. But within a week, the bleeding had become uncontrollable, and the family returned to the hospital. Because the wound would not clot, doctors suspected something was wrong with Mayumi’s blood. They ordered a round of blood work and waited.

  The news was not good. Mayumi tested positive for a grim blood cancer called ALL (acute lymphoblastic leukemia). While most cancers stem from faulty DNA—a cell deletes or miscopies an A, C, G, or T and then turns against the body—Mayumi’s cancer had a more complicated origin. Her DNA had undergone what’s called a Philadelphia translocation (named after the city in which it was discovered in 1960). A translocation takes place when two non-twin chromosomes mistakenly cross over and swap DNA. And unlike a mutational typo, which can occur in any species, this blunder tends to target higher animals with specific genetic features.

  Protein-producing DNA—genes—actually makes up very little of the total DNA in higher animals, as little as 1 percent. Morgan’s fly boys had assumed that genes almost bumped up against each other on chromosomes, strung along tightly like Alaska’s Aleutian Islands. In reality genes are precious rare, scattered Micronesian islands in vast chromosomal Pacifics.

  So what does all that extra DNA do? Scientists long assumed it did nothing, and snubbed it as “junk DNA.” The name has haunted them as an embarrassment ever since. So-called junk DNA actually contains thousands of critical stretches that turn genes on and off or otherwise regulate them—the “junk” manages genes. To take one example, chimpanzees and other primates have short, fingernail-hard bumps (called spines) studding their penises. Humans lack the little prick pricks because sometime in the past few million years, we lost sixty thousand letters of regulatory junk DNA—DNA that would otherwise coax certain genes (which we still have) into making the spines. Besides sparing vaginas, this loss decreases male sensation during sex and thereby prolongs copulation, which scientists suspect helps humans pair-bond and stay monogamous. Other junk DNA fights cancer, or keeps us alive moment to moment.

  To their amazement, scientists even found junk DNA—or, as they say now, “noncoding DNA”—cluttering genes themselves. Cells turn DNA into RNA by rote, skipping no letters. But with the full RNA manuscript in hand, cells narrow their eyes, lick a red pencil, and start slashing—think Gordon Lish hacking down Raymond Carver. This editing consists mostly of chopping out unneeded RNA and stitching the remaining bits together to make the actual messenger RNA. (Confusingly, the excised parts are called “introns,” the included parts “exons.” Leave it to scientists…) For example, raw RNA with both exons (capital letters) and introns (lowercase) might read: abcdefGHijklmnOpqrSTuvwxyz. Edited down to exons, it says GHOST.

  Lower animals like insects, worms, and their ick ilk contain only a few short introns; otherwise, if introns run on for too long or grow too numerous, their cells get confused and can no longer string something coherent together. The cells of mammals show more aptitude here; we can sift through pages and pages of needless introns and never lose the thread of what the exons are saying. But this talent does have disadvantages. For one, the RNA-editing equipment in mammals must work long, thankless hours: the average human gene contains eight introns, each an average of 3,500 letters long—thirty times longer than the exons they surround. The gene for the largest human protein, titin, contains 178 fragments, totaling 80,000 bases, all of which must be stitched together precisely. An even more ridiculously sprawling gene—dystrophin, the Jacksonville of human DNA—contains 14,000 bases of coding DNA among 2.2 million bases of intron cruft. Transcription alone takes sixteen hours. Overall this constant splicing wastes incredible energy, and any slipups can ruin important proteins. In one genetic disorder, improper splicing in human skin cells wipes out the grooves and whorls of fingerprints, rendering the fingertips completely bald. (Scientists have nicknamed this condition “immigration delay disease,” since these mutants get a lot of guff at border crossings.) Other splicing disruptions are more serious; mistakes in dystrophin cause muscular dystrophy.

  Animals put up with this waste and danger because introns give our cells versatility. Certain cells can skip exons now and then, or leave part of an intron in place, or otherwise edit the same RNA differently. Having introns and exons therefore gives cells the freedom to experiment: they can produce different RNA at different times or customize proteins for different environments in the body.* For this reason alone, mammals especially have learned to tolerate vast numbers of long introns.

  But as Mayumi discovered, tolerance can backfire. Long introns provide places for non-twin chromosomes to get tangled up, since there are no exons to worry about disrupting. The Philadelphia swap takes places along two introns—one on chromosome nine, one on chromosome twenty-two—that are exceptionally long, which raises the odds of these stretches coming into contact. At first our tolerant cells see this swap as no big deal, since it’s fiddling “only” with soon-to-be-edited introns. It is a big deal. Mayumi’s cells fused two genes that should never be fused—genes that formed, in tandem, a monstrous hybrid protein that couldn’t do the job of either individual gene properly. The result was leukemia.

  Doctors started Mayumi on chemotherapy at the hospital, but they had caught the cancer late, and she remained quite ill. Worse, as Mayumi deteriorated, their minds started spinning: what about Emiko? ALL is a swift cancer, but not that swift. Mayumi almost certainly had it when pregnant with Emiko. So could the little girl have “caught” the cancer from her mother? Cancer among expectant women is not uncommon, happening once every thousand pregnancies. But none of the doctors had ever seen a fetus catch cancer: the placenta, the organ that connects mother to child, should thwart any such invasion, because in addition to bringing nutrients to the baby and removing waste, the placenta acts as part of the baby’s immune system, blocking microbes and rogue cells.

  Still, a placenta isn’t foolproof—doctors advise pregnant women not to handle kitty litter because Toxo can occasionally slip through the placenta and ravage the fetal brain. And after doing some research and consulting some specialists, the doctors realized that on rare occasions—a few dozen times since the first known instance, in the 1860s—mothers and fetuses came down with cancer simultaneously. No one had ever proved anything about the transmission of these cancers, however, because mother, fetus, and placenta are so tightly bound up that questions of cause and effect get tangled up, too. Perhaps the fetus gave the cancer to the mother in these cases. Perhaps they’d both been exposed to unknown carcinogens. Perhaps it was just a sickening coincidence—two strong genetic predispositions for cancer going off at once. But the Chiba doctors, working in 2006, had a tool no previous generation did: genetic sequencing. And as the Mayumi-Emiko case progressed, these doctors used genetic sequencing to pin down, for the first time, whether or not it’s possible for a mother to give cancer to her fetus. What’s more, their detective work highlighted some functions and mechanisms of DNA unique to mammals, traits that can serve as a springboard
for exploring how mammals are genetically special.

  Of course, the Chiba doctors weren’t imagining their work would take them so far afield. Their immediate concern was treating Mayumi and monitoring Emiko. To their relief, Emiko looked fine. True, she had no idea why her mother had been taken from her, and any breast-feeding—so important to mammalian mothers and children—ceased during chemotherapy. So she certainly felt distress. But otherwise Emiko hit all her growth and development milestones and passed every medical examination. Everything about her seemed, again, normal.

  Saying so might creep expectant mothers out, but you can make a good case that fetuses are parasites. After conception, the tiny embryo infiltrates its host (Mom) and implants itself. It proceeds to manipulate her hormones to divert food to itself. It makes Mom ill and cloaks itself from her immune system, which would otherwise destroy it. All well-established games that parasites play. And we haven’t even talked about the placenta.

  In the animal kingdom, placentas are practically a defining trait of mammals.* Some oddball mammals that split with our lineage long ago (like duck-billed platypi) do lay eggs, just as fish, reptiles, birds, insects, and virtually every other creature do. But of the roughly 2,150 types of mammals, 2,000 have a placenta, including the most widespread and successful mammals, like bats, rodents, and humans. That placental mammals have expanded from modest beginnings into the sea and sky and every other niche from the tropics to the poles suggests that placentas gave them—gave us—a big survival boost.