Time, Love , Memory

by Jonathan Weiner

  In the late 1830s, when Charles Darwin first began scribbling a theory of evolution, his handwriting in his secret notebooks reminded him of the handwriting of his old radical grandfather Erasmus, who had published a theory of evolution the century before. Darwin wondered if he was looking at an “instance of hereditary mind.” His cousin Francis Galton later closed his copy of the Origin wondering if he had just devoured the book because of a “bent of mind that both its illustrious author and myself have inherited from our common grandfather, Dr. Erasmus Darwin.” Darwin and Galton each spent decades compiling examples and anecdotes of what they vaguely called the power of inheritance—vaguely, because even though evolution depended on it, they had no idea how the power of inheritance actually works. They never got much closer to that secret than Galen had, although Darwin’s theory framed the question for those who came after him like the framing of a doorway.

  Until the twentieth century, the passage of time made less difference with this problem than with almost any other basic problem in the study of life. Every argument about nature and nurture was like the mutant fly pirouette, spiraling inward until it died. Every new system of thought that claimed to solve the problem floated apart from every other, cut off from the rest of human knowledge like the brain in Benzer’s workroom, with its severed cord drifting in formaldehyde. The problem was unsolvable before the discovery of the gene.

  THAT DISCOVERY was made by a monk in what is now Brno, in the Czech Republic, in a report on garden peas. Gregor Mendel tended a monastery garden and an experimental greenhouse in the 1850s. While crossing different strains of peas two by two—dusting the flowers of one strain with the pollen of the other—Mendel got a clearer view of the patterns of inheritance than anyone before him. The strains he crossed had smooth peas or wrinkled peas, yellow peas or green; their plant stems were tall or short; and so on: seven pairs of contrasting strains. When Mendel crossed these strains, the traits did not blend together but passed on intact, often skipping several generations. This experiment was so simple that it could have been done by Hippocrates or Democritus, and what made it revolutionary was its demonstration that inheritance comes in something like the Greek idea of atoms. Tallness never blended with shortness. They do blend in humans, but they don’t blend in peas—one reason Mendel was lucky to work with peas. There the patterns stayed crisp and clear. The traits stayed separate generation after generation, and Mendel assumed that they must be governed by separate factors. Much later, biologists who reread Mendel’s paper would think of these factors, with a nod to physics and chemistry, as particles of inheritance. No one knows how the monk pictured them, although he, like Benzer, had been trained as a physicist.

  Thirty years ago, Benzer and another founder of molecular biology, Gunther Stent, climbed Mount Fuji, a climb that Benzer still remembers fondly because on it he tasted his first mandarin orange. They stopped for the night in a Buddhist temple halfway up the volcano. The temple’s caretaker was an ancient woman, who asked Benzer and Stent, through their interpreter, what they did. As they began to explain, she said, “Ah, Mendel.”

  While Mendel planted peas, Francis Galton, Darwin’s cousin, caught glimpses of the particles of inheritance in human beings. Reading the Origin had inspired Galton to send out hundreds of letters and questionnaires to friends, acquaintances, acquaintances of acquaintances, asking about family resemblances and especially about twins. Galton spent the rest of his life collecting such data and inventing new statistical tools to analyze the patterns. Along the way he sent Darwin an example of behavior that skipped generations:

  A gentleman of considerable position was found by his wife to have the curious trick, when he lay fast asleep on his back in bed, of raising his right arm slowly in front of his face, up to his forehead, and then dropping it with a jerk, so that the wrist fell heavily on the bridge of his nose. The trick did not occur every night, but occasionally, and was independent of any ascertained cause. Sometimes it was repeated incessantly for an hour or more. The gentleman’s nose was prominent, and its bridge often became sore from the blows which it received.…

  Many years after his death, his son married a lady who had never heard of the family incident. She, however, observed precisely the same peculiarity in her husband; but his nose, from not being particularly prominent, has never as yet suffered from the blows.…

  One of his children, a girl, has inherited the same trick.

  “We seem to inherit bit by bit,” Galton concluded in 1889 in his book Natural Inheritance. That was the only way Galton could interpret the peculiar persistence of bits of family resemblance and bits of behavior. But the patterns of inheritance in his data were not as clean and clear-cut as they were in Mendel’s experiments; and neither Galton nor Darwin ever read his paper, which was published in the journal of Mendel’s local natural history society in 1866.

  No one realized what Mendel’s paper might mean for the inheritance problem until a botanist cited it in a paper in January 1900. By then the time was right, and two other citations followed that same year. All three papers attracted attention, although the existence of atomic particles was still considered speculative, and so was the existence of Mendel’s particles of inheritance. One of the biologists who read the new papers closely but skeptically was Thomas Hunt Morgan, born in Lexington, Kentucky, in 1866, the same year that Mendel had published his paper.

  In the fall of 1907, Morgan, then a professor of zoology at Columbia University, told one of his students to put a few bananas on the ledge of his laboratory window to attract some fruit flies. Neither teacher nor student was thinking about Mendel at the time; the student wanted to breed animals in the dark and see if they would lose their instinct to go toward light. Morgan told him to use fruit flies because his laboratory in Schermerhorn Hall was cramped, only about sixteen by twenty-three feet. It was cramped and crowded because Morgan, who had been trained as an old-fashioned naturalist, already took pleasure in working with pigeons, chickens, starfish, rats, and yellow mice.

  So Morgan’s student Fernandus Payne trapped some flies, put them in darkness, and let them breed. Within a short time he thought he could detect a change. The tenth generation seemed to move toward the light a little more slowly than the first. This student project, which Payne wrote up in a paper, “Forty-nine Generations in the Dark,” was soon lost in the late prehistory of genetics. Benzer knew nothing about it in 1966 when he built his countercurrent machine.

  Next Morgan decided to see if he could force fruit flies to change faster. Morgan had money, but he was a miser in the laboratory, which was another reason he liked working with flies. For microscope lamps, he used ordinary lightbulbs with shades that he and Payne cut out of tin cans. For fly bottles, according to legend, he and his students stole empty half-pints from milk boxes on Manhattan stoops on their early-morning walks to the lab, and they lifted more from the Columbia student cafeteria. This was the milk-bottle tradition that Benzer would inherit.

  Morgan subjected his flies to heat, cold, and X rays, trying to create a fly that looked different in some way from all the other flies. He also injected the flies’ private parts with acids, bases, salts, sugars, and alcohol. Beneath the hand lens each fly had the same six legs, the same veined and cross-veined wings, the same brilliant red eyes; but Morgan kept watching and waiting for a mutant. And this was the enterprise that Benzer would inherit, although Benzer would manipulate his flies with more sophistication, and he would watch for changes not in their bodies but in their behavior.

  Early in the fall of 1909, Morgan began trying to speed up the evolution of his flies with a new approach. He focused on a dark pattern on the thorax of the fly, a variable pattern in the shape of a trident. Week after week he bred only those flies with the most variable tridents and waited to see if the pressure of this artificial selection would somehow set off an explosion of mutations in one of his fly bottles. Week after week, he and Payne saw nothing but ordinary tridents on ordinary flies.

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bsp; “There’s two years’ work wasted,” Morgan told a visitor in the first days of January 1910, waving at shelves of stolen milk bottles. But just a few days later, Morgan found a fly with a trident that was slightly darker and more sharply defined than before. Then he found a fly that had a dark blotch where the wing met the thorax. Then, after all those tens of thousands of more or less identical red-eyed flies, he found a single fly with white eyes.

  Morgan’s wife, Lilian, who was fascinated by his work and who later (after their children were out of the house and busy in school) made important contributions in the laboratory, was pregnant that year; and long afterward the birth of the new baby became mingled in the family history with the arrival of the mutant. Lilian loved to recall the scene when Morgan walked into her hospital room.

  “Well, how is the white-eyed fly?” she asked. According to family lore, he was carrying the fly home at night to sleep in a jar next to their bed.

  Morgan told her the fly looked feeble but it was hanging on. “And how is the baby?”

  Within a week, one of their two new arrivals was old enough to breed (still another reason to work with flies). Morgan paired the white-eyed fly, which was a male, with normal virgin female flies, and together they produced 1,237 young flies. The flies’ children (as Morgan called them) had red eyes. The next week, Morgan arranged marriages for the children. He was fascinated to see that among the grandchildren, although all of the females had red eyes, about one in two of the males had white eyes. Naturally Morgan thought of Mendel’s peas. When Mendel crossed short peas with tall peas, the first generation was all tall, and in the next generation three quarters of the plants were tall and one quarter was short. Shortness in Mendel’s pea plants is what is now known as a recessive trait, like blue eyes among human beings. Morgan wondered if white eyes among male fruit flies could be a recessive trait too.

  As one latter-day drosophilist likes to say now, “In the beginning there was white.” The mutant fly white was the point of entry through which Morgan would establish the modern theory of the gene, the atomic theory of inheritance. In much the same way, decades later, the arrival of the first clock mutant, a fly without a sense of time, would open the atomic theory of behavior. That mutant would give Benzer a point of entry through which he and his students could begin the remarkable series of experiments in which they took basic instincts apart and put them back together, like clock makers who had unscrewed the back of a clock.

  The arrival of white intrigued Morgan because ever since 1900, biologists had been looking for Mendel’s elements. Through microscopes they could see tiny threads called chromosomes in the nucleus of every egg. They could also see that when a spermatozoan enters an egg, it contributes a matching set of threads. To many biologists, this looked like a physical explanation for Mendel’s results in his pea garden. A pea plant might inherit a tallness factor on one chromosome, for example, and a shortness factor on the other chromosome in that particular pair. The logic seemed compelling: Mendel saw traits in pairs; microscopists saw chromosomes in pairs. And when a young body begins making new eggs or new sperm, each egg cell and sperm cell receives only one chromosome from each chromosome pair. That way, when sperm finds egg, the single chromosomes can meet inside the fertilized egg and the whole process can start over to make a new life.

  All of this fit Mendel’s observations. But Morgan was a contrarian. He used to complain that his best friends at Columbia were “wild over chromosomes.” It did look as if chromosomes were “the thing,” he said, but he wanted hard evidence: “I cannot but fear that we are rapidly developing a sort of Mendelian ritual by which to explain the extraordinary facts.” Morgan’s “show-me” attitude was about to lead him into the simple line of experiments that started the revolution in twentieth-century biology. It was the same attitude that Benzer would later bring to the study of genes and behavior in his own Fly Room. Feynman, the quantum physicist, once knocked on the door of Benzer’s workroom and asked him to show his son a fly’s brain. Benzer sat the boy at a microscope and told him, “There’re a hundred thousand transistors in that brain.” Benzer’s own work as a physicist had helped lead to the invention of the transistor. By comparing the fly’s one hundred thousand neurons to transistors, Benzer was trying to convey an idea of the fly brain’s magnificent miniaturization. At the same time Benzer was also nodding to the father over the son’s head, physicist to physicist.

  But Feynman said, “No, no. Tell it straight. They’re not transistors, they’re neurons. Don’t oversimplify.”

  Benzer liked that line too. Feynman was right. A neuron is actually a much more complicated object than a transistor, and the path from gene to neuron and from neuron to behavior is longer and more mysterious than the path from an electron to a radio or a computer. Benzer shared with Feynman an aggressively simple and direct style of talking—a trait both men also shared with T. H. Morgan. Benzer and Feynman came from families of New York Jews, Eastern European immigrants; Morgan came from an old family of Kentucky aristocrats. But all three spoke in the kind of down-home, common-as-flies style that is the lingua franca of great scientists, conveying a contempt for pretension, a contempt for cant, a delight in common sense, combined with uncommon curiosity about what is really there.

  Sitting in his first Fly Room in Columbia’s Schermerhorn Hall, T. H. Morgan could see through his microscope that a fruit fly has four pairs of chromosomes. In female flies, all four pairs look alike: short, featureless threads. But in male flies, the fourth pair looks different: one is bigger than the other. This is the chromosome pair that is now known, famously, as the X and the Y. Morgan focused on this mismatched fourth pair. He knew that a fly, like a pea plant or a human being, always inherits one chromosome from each parent. In each pair, one chromosome comes from the father and one from the mother. Since a female fly has two Xs and a male has an X and a Y, Morgan could deduce that a son must inherit his X from his mother and his Y from his father. If his father has white eyes and his mother has red eyes, then he will have red eyes. But if his father has red eyes and his mother has white, then he will have white eyes. So Morgan wondered if the fly has a gene for eye color on the X chromosome.

  In his Fly Room at Columbia University, in the early years of the twentieth century, Thomas Hunt Morgan transformed the study of life. Because Morgan hated being photographed, his students stole this picture by hiding the camera in an incubator and pulling a string. The camera, along with the books and microscopes that are visible behind Morgan, belonged to his favorite student, Alfred Sturtevant, whose eureka one night in 1911 helped establish the theory of the gene. (Illustrations credit 2.1)

  A female fly gets one X chromosome from each of her parents. If her mother gives her an X with a gene for white eyes and her father also gives her an X with a gene for white eyes, then she will have white eyes. But if either of her parents gives her an X with a gene for red eyes, then she will have red eyes, because red is dominant over white in flies, just as purple is dominant over white in the flowers of Mendel’s pea plants.

  Human beings have many more pairs of chromosomes (twenty-three pairs, although Morgan’s generation could not sort them out and count them properly). Twenty-two of those twenty-three pairs look like identical twin threads under the microscope. The last pair is mismatched, just as it is in flies: two X chromosomes in women, an X and a Y in men. And color blindness in men, Morgan realized, as he thought about all this, “follows the same scheme as does white eyes in my flies.”

  Morgan began to suspect that genes might exist, and that there really might be a gene for eye color hidden somewhere on the fly’s X chromosome. By now he and his first students had examined so many flies through their hand lenses and microscopes that the slightest aberration leaped out, and they began to find more and more mutants in their fly bottles. One was a fly with abnormally short wings. When Morgan bred it he saw that wing length, like eye color, seemed to be on the X.

  Now Morgan experimented with these mutants. Su
ppose a female has red eyes and long wings: she is a normal fly. Suppose a male has white eyes and short wings: he is a double mutant. If they mate, every one of their daughters will inherit one X from the mother and one X from the father. So, since red and long are dominant over white and short, the daughters should have red eyes and long wings, too. Morgan arranged that cross, and so it was.

  Morgan thought he knew exactly what was on each of those two Xs, if the gene theory was correct. One X carried genes for red eyes and long wings; the other X carried genes for white eyes and short wings. If so, then when these normal-looking females mated with normal males, each mother should produce just two kinds of sons, depending on which X each son inherited. Some of the sons should be normal like their mother; some of the sons should be double mutants like their grandfather.

  Morgan arranged this cross. Just as he expected, some of the sons were normal and some were double mutants. But others had white eyes and normal wings, and still others had red eyes and short wings: they were single mutants. At first sight, that seemed impossible. Each of the sons could inherit just one X from his mother, and his mother did not have an X with a white gene and a long gene, or an X with a red gene and a short gene. It was as if the mother had mixed and matched bits of her two Xs before passing out an X to each of her sons.

  After much thought, Morgan could explain that. He considered the microscopic action that takes place when a female fly makes an egg. Her egg has to receive four chromosomes, one strand apiece from each of her four pairs of chromosomes. But the specialized cell that prepares the chromosomes for the new egg has the chromosomes in pairs. So to produce the egg, in the process known as meiosis, each of those pairs of chromosomes has to split up. Just before they part, each pair does something almost gaudily bizarre. The two strands twist and twine around each other as if they themselves are mating. They writhe together like copulating snakes.