The Violinist's Thumb: And Other Lost Tales of Love, War, and Genius, as Written by Our Genetic Code (22 page)

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.
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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.
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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.

As probably its biggest benefit, the placenta allows a
mammal mother to carry her living, growing children within her. As a result she can keep her children warm inside the womb and run away from danger with them, advantages that spawning-into-water and squatting-on-nest creatures lack. Live fetuses also have longer to gestate and develop energy-intensive organs like the brain; the placenta’s ability to pump bodily waste away helps the brain develop, too, since fetuses aren’t stewing in toxins. What’s more, because she invests so much energy in her developing fetus—not to mention the literal and intimate connection she feels because of the placenta—a mammal mom feels incentive to nurture and watch over her children, sometimes for years. (Or at least feels the need to nag them for years.) The length of this investment is rare among animals, and mammal children reciprocate by forming unusually strong bonds to their mothers. In one sense, then, the placenta, by enabling all this, made us mammals caring creatures.

That makes it all the more creepy that the placenta, in all likelihood, evolved from our old friends the retroviruses. But from a biological standpoint, the connection makes sense. Clamping on to cells happens to be a talent of viruses: they fuse their “envelopes” (their outer skin) to a cell before injecting their genetic material into it. When a ball of embryonic cells swims into the uterus and anchors itself there, the embryo also fuses part of itself with the uterine cells, by using special fusion proteins. And the DNA that primates, mice, and other mammals use to make the fusion proteins appears to be plagiarized from genes that retroviruses use to attach and meld their envelopes. What’s more, the uterus of placental mammals draws heavily on other viruslike DNA to do its job, using a special jumping gene called
mer20
to flick 1,500 genes on and off in uterine cells. With both organs, it seems we once again borrowed some handy genetic material from a parasite and adapted it to our own ends. As a bonus, the viral genes in the placenta even provide extra
immunity, since the presence of retrovirus proteins (either by warning them off, or outcompeting them) discourages other microbes from circling the placenta.

As another part of its immune function, the placenta filters out any cells that might try to invade the fetus, including cancer cells. Unfortunately, other aspects of the placenta make it downright attractive to cancer. The placenta produces growth hormones to promote the vigorous division of fetal cells, and some cancers thrive on these growth hormones, too. Furthermore, the placenta soaks up enormous amounts of blood and siphons off nutrients for the fetus. That means that blood cancers like leukemia can lurk inside the placenta and flourish. Cancers genetically programmed to metastasize, like the skin cancer melanoma, take to the blood as they slither around inside the body, and they find the placenta quite hospitable as well.

In fact, melanoma is the most common cancer that mothers and fetuses get simultaneously. The first recorded simultaneous cancer, in 1866, in Germany, involved a roaming melanoma that randomly took root in the mother’s liver and the child’s knee. Both died within nine days. Another horrifying case claimed a twenty-eight-year-old Philadelphia woman, referred to only as “R. McC” by her doctors. It all started when Ms. McC got a brutal sunburn in April 1960. Shortly afterward a half-inch-long mole sprung up between her shoulder blades. It bled whenever she touched it. Doctors removed the mole, and no one thought about it again until May 1963, when she was a few weeks pregnant. During a checkup, doctors noticed a nodule beneath the skin on her stomach. By August the nodule had widened even faster than her belly, and other, painful nodules had sprung up. By January, lesions had spread to her limbs and face, and her doctors opened her up for a cesarean section. The boy inside appeared fine—a full seven pounds, thirteen ounces. But his mother’s abdomen was spotted with dozens of tumors, some of
them black. Not surprisingly, the birth finished off what little strength she had. Within an hour, her pulse dropped to thirty-six beats per minute, and though her doctors resuscitated her, she died within weeks.

And the McC boy? There was hope at first. Despite the widespread cancer, doctors saw no tumors in Ms. McC’s uterus or placenta—her points of contact with her son. And although he was sickly, a careful scan of every crevice and dimple revealed no suspicious-looking moles. But they couldn’t check inside him. Eleven days later tiny, dark blue spots began breaking out on the newborn’s skin. Things deteriorated quickly after that. The tumors expanded and multiplied, and killed him within seven weeks.

Mayumi had leukemia, not melanoma, but otherwise her family in Chiba reprised the McC drama four decades later. In the hospital, Mayumi’s condition deteriorated day by day, her immune system weakened by three weeks of chemotherapy. She finally contracted a bacterial infection and came down with encephalitis, inflammation of the brain. Her body began to convulse and seize—a result of her brain panicking and misfiring—and her heart and lungs faltered, too. Despite intensive care, she died two days after contracting the infection.

Even worse, in October 2006, nine months after burying his wife, Hideo had to return to the hospital with Emiko. The once-bouncing girl had fluid in her lungs and, more troublesome, a raw, fever-red mass disfiguring her right cheek and chin. On an MRI, this premature jowl looked enormous—as large as tiny Emiko’s brain. (Try expanding your cheek as far as it will go with air, and its size still wouldn’t be close.) Based on its location within the cheek, the Chiba doctors diagnosed sarcoma, cancer of the connective tissue. But with Mayumi in the back of their minds, they consulted experts in Tokyo and England and decided to screen the tumor’s DNA to see what they could find.

They found a Philadelphia swap. And not just any Philadelphia
swap. Again, this crossover takes place along two tremendously long introns, 68,000 letters long on one chromosome, 200,000 letters long on the other. (This chapter runs about 30,000 letters.) The two arms of the chromosomes could have crossed over at any one of thousands of different points. But the DNA in both Mayumi’s and Emiko’s cancer had crossed over at the same spot, down the same letter. This wasn’t chance. Despite lodging in Emiko’s cheek, the cancer basically was the same.