The Violinist's Thumb: And Other Lost Tales of Love, War, and Genius, as Written by Our Genetic Code (9 page)

RNA Tie Club members sporting green wool ties with gold silk RNA embroidery. From left, Francis Crick, Alexander Rich, Leslie E. Orgel, James Watson. (Courtesy of Alexander Rich)

Despite its collective intellectual horsepower, in one way the club ended up looking a little silly historically. Problems of perverse complexity often attract physicists, and certain physics-happy club members (including Crick, a physics Ph.D.) threw themselves into work on DNA and RNA before anyone realized how simple the DNA → RNA → proteins process was. They concentrated especially on how DNA stores its instructions, and for whatever reason they decided early on that DNA must conceal its instructions in an intricate code—a biological cryptogram. Nothing excites a boys’ club as much as coded messages, and like ten-year-olds with Cracker Jack decoder rings, Gamow, Crick, and others set out to break this cipher. They were soon scribbling away with pencil and paper at their desks, page after page piling up, their imaginations happily unfettered by doing experiments. They devised solutions clever enough to make Will Shortz smile—“diamond codes” and “triangle codes” and “comma codes” and many forgotten others. These were NSA-ready codes, codes with reversible messages, codes with error-correction mechanisms built in, codes that maximized storage
density by using overlapping triplets. The RNA boys especially loved codes that used equivalent anagrams (so CAG = ACG = GCA, etc.). The approach was popular because when they eliminated all the combinatorial redundancies, the number of unique triplets was exactly twenty. In other words, they’d seemingly found a link between twenty and sixty-four—a reason nature just
had to
use twenty amino acids.

In truth, this was so much numerology. Hard biochemical facts soon deflated the code breakers and proved there’s no profound reason DNA codes for twenty amino acids and not nineteen or twenty-one. Nor was there any profound reason (as some hoped) that a given triplet called for a given amino acid. The entire system was accidental, something frozen into cells billions of years ago and now too ingrained to replace—the
QWERTY
keyboard of biology. Moreover, RNA employs no fancy anagrams or error-correcting algorithms, and it doesn’t strive to maximize storage space, either. Our code is actually choking on wasteful redundancy: two, four, even six RNA triplets can represent the same amino acid.
^*
A few biocryptographers later admitted feeling annoyed when they compared nature’s code to the best of the Tie Club’s codes. Evolution didn’t seem nearly as clever.

Any disappointment soon faded, however. Solving the DNA/RNA code finally allowed scientists to integrate two separate realms of genetics, gene-as-information and gene-as-chemical, marrying Miescher with Mendel for the first time. And it actually turned out better in some ways that our DNA code is kludgy. Fancy codes have nice features, but the fancier a code gets, the more likely it will break down or sputter. And however crude, our code does one thing well: it keeps life going by minimizing the damage of mutations. It’s exactly that talent that Tsutoma Yamaguchi and so many others had to count on in August 1945.

Ill and swooning, Yamaguchi arrived in Nagasaki early on August 8 and staggered home. (His family had assumed him lost; he convinced his wife he wasn’t a ghost by showing her his feet, since Japanese ghosts traditionally have none.) Yamaguchi rested that day, swimming in and out of consciousness, but obeyed an order the next day to report to Mitsubishi headquarters in Nagasaki.

He arrived shortly before 11 a.m. Arms and face bandaged, he struggled to relate the magnitude of atomic warfare to his coworkers. But his boss, skeptical, interrupted to browbeat him, dismissing his story as a fable. “You’re an engineer,” he barked. “Calculate it. How could one bomb… destroy a whole city?” Famous last words. Just as this Nostradamus wrapped up, a white light swelled inside the room. Heat prickled Yamaguchi’s skin, and he hit the deck of the ship-engineering office.

“I thought,” he later recalled, “the mushroom cloud followed me from Hiroshima.”

Eighty thousand people died in Hiroshima, seventy thousand more in Nagasaki. Of the hundreds of thousands of surviving victims, evidence suggests that roughly 150 got caught near both cities on both days, and that a handful got caught within both blast zones, a circle of intense radiation around 1.5 miles wide. Some of these
nijyuu hibakusha,
double-exposure survivors, had stories to make stones weep. (One had burrowed into his wrecked home in Hiroshima, clawed out his wife’s blackened bones, and stacked them in a washbasin to return them to her parents in Nagasaki. He was trudging up the street to the parents’ house, washbasin under his arm, when the morning air again fell quiet and the sky was once again bleached white.) But of all the reported double victims, the Japanese government has recognized only one official
nijyuu hibakusha,
Tsutomu Yamaguchi.

Shortly after the Nagasaki explosion, Yamaguchi left his shaken boss and office mates and climbed a watchtower on a nearby hill. Beneath another pall of dirty clouds, he watched his cratered-out hometown smolder, including his own house. A tarry radioactive rain began falling, and he struggled down the hill, fearing the worst. But he found his wife, Hisako, and young son, Katsutoshi, safe in an air-raid shelter.

After the exhilaration of seeing them wore off, Yamaguchi felt even more ill than before. In fact, over the next week he did little but lie in the shelter and suffer like Job. His hair fell out. Boils erupted. He vomited incessantly. His face swelled. He lost hearing in one ear. His reburned skin flaked off, and beneath it his flesh glowed raw red “like whale meat” and pierced him with pain. And as badly as Yamaguchi and others suffered during those months, geneticists feared the long-term agony would be equally bad, as mutations slowly began surfacing.

Scientists had known about mutations for a half century by then, but only work on the DNA → RNA → protein process by the Tie Club and others revealed exactly what these mutations consisted of. Most mutations involve typos, the random substitution of a wrong letter during DNA replication: CAG might become CCG, for instance. In “silent” mutations, no harm is done because of the DNA code’s redundancy: the before and after triplets call for the same amino acid, so the net effect is like mistyping
grey
for
gray.
But if CAG and CCG lead to different amino acids—a “missense” mutation—the mistake can change a protein’s shape and disable it.

Even worse are “nonsense” mutations. When making proteins, cells will continue to translate RNA into amino acids until they encounter one of three “stop” triplets (e.g., UGA), which terminate the process. A nonsense mutation accidentally turns a normal triplet into one of these stop signs, which truncates the protein early and usually disfigures it. (Mutations can also undo
stop signs, and the protein runs on and on.) The black mamba of mutations, the “frameshift” mutation, doesn’t involve typos. Instead a base disappears, or an extra base squeezes in. Because cells read RNA in consecutive groups of three, an insertion or deletion screws up not only that triplet but every triplet down the line, a cascading catastrophe.

Cells usually correct simple typos right away, but if something goes wrong (and it will), the flub can become permanently fixed in DNA. Every human being alive today was in fact born with dozens of mutations his parents lacked, and a few of those mutations would likely be lethal if we didn’t have two copies of every gene, one from each parent, so one can pick up the slack if the other malfunctions. Nevertheless all living organisms continue to accumulate mutations as they age. Smaller creatures that live at high temperatures are especially hard hit: heat on a molecular level is vigorous motion, and the more molecular motion, the more likely something will bump DNA’s elbow as it’s copying. Mammals are relatively hefty and maintain a constant body temperature, thankfully, but we do fall victim to other mutations. Wherever two T’s appear in a row in DNA, ultraviolet sunlight can fuse them together at an odd angle, which kinks DNA. These accidents can kill cells outright or simply irritate them. Virtually all animals (and plants) have special handyman enzymes to fix T-T kinks, but mammals lost them during evolution—which is why mammals sunburn.

Besides spontaneous mutations, outside agents called mutagens can also injure DNA, and few mutagens do more damage than radioactivity. Again, radioactive gamma rays cause free radicals to form, which cleave the phosphate-sugar backbone of DNA. Scientists now know that if just one strand of the double helix snaps, cells can repair the damage easily, often within an hour. Cells have molecular scissors to snip out mangled DNA, and can run enzymes down the track of the undamaged strand
and add the complementary A, C, G, or T at each point. The repair process is quick, simple, and accurate.

Double-strand breaks, though rarer, cause direr problems. Many double breaks resemble hastily amputated limbs, with tattered flaps of single-stranded DNA hanging off both ends. Cells do have two near-twin copies of every chromosome, and if one has a double-strand break, cells can compare its ragged strands to the (hopefully undamaged) other chromosome and perform repairs. But this process is laborious, and if cells sense widespread damage that needs quick repairs, they’ll often just slap two hanging flaps together wherever a few bases line up (even if the rest don’t), and hastily fill in the missing letters. Wrong guesses here can introduce a dreaded frameshift mutation—and there are plenty of wrong guesses. Cells repairing double-strand breaks get things wrong roughly three thousand times more often than cells simply copying DNA.

Even worse, radioactivity can delete chunks of DNA. Higher creatures have to pack their many coils of DNA into tiny nuclei; in humans, six linear feet cram into a space less than a thousandth of an inch wide. This intense scrunching often leaves DNA looking like a gnarly telephone cord, with the strand crossing itself or folding back over itself many times. If gamma rays happen to streak through and snip the DNA near one of these crossing points, there will be multiple loose ends in close proximity. Cells don’t “know” how the original strands lined up (they don’t have memories), and in their haste to fix this catastrophe, they sometimes solder together what should be separate strands. This cuts out and effectively deletes the DNA in between.

So what happens after these mutations? Cells overwhelmed with DNA damage can sense trouble and will kill themselves rather than live with malfunctions. This self-sacrifice can spare the body trouble in small doses, but if too many cells die at once, whole organ systems might shut down. Combined with intense
burns, these shutdowns led to many deaths in Japan, and some of the victims who didn’t die immediately probably wished they had. Survivors remember seeing people’s fingernails fall off whole, dropping from their fists like dried shell pasta. They remember human-sized “dolls of charcoal” slumped in alleys. Someone recalled a man struggling along on two stumps, holding a charred baby upside down. Another recalled a shirtless woman whose breasts had burst “like pomegranates.”

During his torment in the air-raid shelter in Nagasaki, Yamaguchi—bald, boily, feverish, half deaf—nearly joined this list of casualties. Only dedicated nursing by his family pulled him through. Some of his wounds still required bandages and would for years. But overall he traded Job’s life for something like Samson’s: his sores mostly healed, his strength returned, his hair grew back. He began working again, first at Mitsubishi, later as a teacher.

Far from escaping unscathed, however, Yamaguchi now faced a more insidious, more patient threat, because if radioactivity doesn’t kill cells outright, it can induce mutations that lead to cancer. That link might seem counterintuitive, since mutations generally harm cells, and tumor cells are thriving if anything, growing and dividing at alarming rates. In truth all healthy cells have genes that act like governors on engines, slowing down their rpm’s and keeping their metabolisms in check. If a mutation happens to disable a governor, the cell might not sense enough damage to kill itself, but eventually—especially if other genes, like those that control how often a cell divides, also sustain damage—it can start gobbling up resources and choking off neighbors.

Many survivors of Hiroshima and Nagasaki absorbed doses of radiation a hundred times higher—and in one gulp—than the background radiation a normal person absorbs in a year. And the closer survivors got caught to the epicenter, the more deletions
and mutations appeared in their DNA. Predictably, cells that divide rapidly spread their DNA damage more quickly, and Japan saw an immediate spike in leukemia, a cancer of prolific white blood cells. The leukemia epidemic started to fade within a decade, but other cancers gained momentum in the meantime—stomach, colon, ovary, lung, bladder, thyroid, breast.

As bad as things were for adults, fetuses proved more vulnerable: any mutation or deletion in utero multiplied over and over in their cells. Many fetuses younger than four weeks spontaneously aborted, and among those that lived, a rash of birth defects, including tiny heads and malformed brains, appeared in late 1945 and early 1946. (The highest measured IQ among the handicapped ones was 68.) And on top of everything else, by the late 1940s, many of the quarter-million
hibakusha
in Japan began to have new children and pass on their exposed DNA.