Time, Love , Memory

by Jonathan Weiner

  The letter came from Jerry Hirsch, a behavior geneticist at the University of Illinois in Urbana. Hirsch was a strong polemicist against eugenics and racism. He had learned from one of Morgan’s Raiders, Theodosius Dobzhansky, to think of genetics as a powerful argument against prejudice of all kinds. Hirsch had once published a manifesto on the subject in Science, back in 1963, while Benzer was still feeling his way from rII toward behavior. In fact, in Hirsch’s manifesto, “Behavior Genetics and Individuality Understood,” he had used Benzer’s rII work to calculate that the probability that two parents will have a second child genetically identical to their first is less than one in 70 trillion. “Individual differences are no accident,” Hirsch argued, and every individual is so distinctive that racism is intellectually bankrupt: “The concept of a normal individual has no generality.” Hirsch had spent years breeding fruit flies for changes in their instinct to turn upward rather than downward in a vertical maze: geotaxis. He ran his flies through the maze individually, and he hoped that by dramatizing the genetic diversity that underlies behavior, his experiment would strike another blow against racism.

  Benzer’s countercurrent machine had been inspired in part by Hirsch’s vertical labyrinth. But Benzer was looking for mutants that might provide a point of entry into the molecular basis of an instinct. In this way Benzer was working toward a goal that was out of reach for Hirsch. Traditional behavior geneticists like Hirsch worked with the tools of yet another branch of the science that Mendel and Morgan started, a branch known as population genetics, which is strongly mathematical. After a statistical analysis of his breeding study, Hirsch could not map the genes involved in an instinct like geotaxis. He could conclude, for instance, that no more than two or three genes seemed to make the difference. But he could not find the genes themselves. He had to “declare victory and retreat,” as one of Benzer’s students’ students once put it, whereas Benzer could find single genes and then map them, hoping eventually to use them to split behavior patterns into pieces, dissect them, and see how they work.

  In the Vancouver letter, Hirsch criticized Benzer for herding squads of flies through his machine. Benzer was behaving as if the flies were genetically homogeneous, except for a few oddball mutants. In this way Benzer was committing what Hirsch often called “the uniformity assumption,” the original sin not only of many failed behavior studies but also of racism.

  Hirsch thought his disagreements with Benzer ran deep, although Benzer had trouble understanding most of them. Hirsch had also spoken at the Vancouver meeting. “Hirsch traditionally gave some kind of bigwig talk,” says a former student of Hirsch, Tim Tully, who later went over to the Benzer camp. “This was his meeting, OK?” But the conference organizers had asked Benzer, not Hirsch, to give the plenary address. Tully, who was an undergraduate student at the University of Illinois a few years before the episode, remembers Hirsch pulling him into his office once in 1973, saying, “I’ve got it, I’ve got it.” Hirsch showed Tully a Scientific American article by Benzer, “Genetic Dissection of Behavior.” Hirsch read him Benzer’s whimsical description of a one-eyed fly that makes a helix as it runs up a tube toward a light. Hirsch told Tully—with what Tully remembers as an unnerving intensity—that Benzer had written “clockwise” when he should have written “counterclockwise.” Tully walked away, mulled over Hirsch’s argument, and realized that Benzer was right. Tully still remembers the moment he broke the news to his professor. “He was about to launch another letter. He stood up and closed the door in my face.”

  “I really didn’t understand,” Benzer says now. “I thought it was way off base, trying to ruin my reputation with my colleagues. When somebody denounces you like that, everyone thinks, quite aside from the facts of the matter, ‘Well, you know …’ There’s always this doubt: ‘Maybe the guy has something,’ ” Benzer says. He sensed that doubt in his colleagues whenever he tried to talk with them about the letter. Eventually he decided to give a department seminar to clear the air. The talk was standing room only. It was not a success. “I don’t think I did a very good job,” Benzer says now. “I tried to explain everything from both sides, and it did not go over very well.”

  Konrad Lorenz liked to describe the territorial disputes of male sticklebacks defending their nests. With sticklebacks as with academics, a property dispute is a ritualized head-to-head dance that seldom draws actual blood. “The pursuit is repeated a few times in alternating directions,” Lorenz wrote, “swinging to and fro like a pendulum which at last reaches a state of equilibrium at a certain point.” By sending such a public letter, Hirsch was going head-to-head with Benzer, and the battle might have been expected to swing back and forth for years. But after that one failed seminar, Benzer did not mount a counterchase. Instead he let the learning-and-memory work go, along with all the rest of his mutant behavior work. Although he does not say so, it was a bad time for him, the year after Dotty’s death. His two daughters were grown and gone. For the first time in his life, he was coming home from the lab at dawn to empty rooms.

  “Well, people said, ‘This man just craves attention,’ ” Benzer says today. “Roger Sperry told me, ‘Don’t give him attention, or there’ll be no end to it.’ So, I just gradually forgot about it. A memory like that decays rather slowly. Now I’m glad that my reputation has survived somehow.”

  For years, Hirsch would continue to argue that Benzer and his students were hopelessly misguided, even after their discoveries began appearing almost monthly on the covers of Science, Nature, Cell, and Neuron. When asked about the science that Benzer had started, Hirsch would say, “It’s certainly moving. Maybe not forward.”

  And for years, Benzer would keep a distance from the atomic theory of behavior. He decided to make a fresh start, as he had done so many times before. When he turned away from electronics, his interest had shut off like a tap. He had turned away from gene mapping in the same way, and after Dotty died he could not bear to think about cancer.

  In his sanctum at Church Hall, Benzer lost himself in the microcosm in which he felt increasingly at home. Through the microscope he studied the eye of the fly. Each fly eye has eight hundred facets called “ommatidia.” Each ommatidium is a hexagon, and at high power he could see inside each hexagon a bundle of eight cells in the shape of a trapezoid, with six cells on the outside, R1 through R6, and two on the inside, R7 and R8.

  Again and again he watched the living cells of a fly embryo build this structure. Again and again he watched the eye grow as if it were the latticework of a living crystal, a neurocrystal. He could actually see the nerve cells’ nuclei bobbing up and down inside them as they chose their places and decided their fates one by one inside the growing dome.

  Benzer had imagined that to build such an elaborate neurocrystal, the genes and cells must work like cogwheels, like clockwork, like atoms falling into place in inorganic crystals with absolute regularity. But even in the eye of the fly, he was amazed to see the nerve cells making decisions and revisions based on where they were at each particular moment and what was happening around them. It was almost like watching the flies in his countercurrent machine. And here, too, there were mutants. A mutant fly called sevenless was discovered by two of Benzer’s graduate students, William Harris and Donald Ready (who devoted his Ph.D. work to the eye of the fly). In sevenless, a nerve cell that by rights should become R7 strays off instead to another fate. Instead of a photoreceptor cell, it becomes a cell that cannot detect light, and it helps make the lens of the ommatidium. In other words, R7 behaves very much like a fly that turns toward the darkness instead of the light. A single mutation makes the difference.

  WHILE BENZER was exploring the eye of the fly, he met Carol Miller, a neuropathologist who worked across town at the University of Southern California School of Medicine. She was almost twenty years younger, and Benzer thought she looked like the woman in a painting he loved, Vermeer’s Woman with a Turban. They soon discovered that they shared an obsession with the machinery of the brain. T
hey both liked the same kinds of novelties and gewgaws, too: a plastic brain with a compass in it; a plastic eyeball key chain; a brain-shaped Jell-O mold. They both liked the same books: Human Oddities; Smith’s Recognizable Patterns of Human Malformation; and Sideshow, which has photographs of dwarfs, midgets, giants, women with beards, a woman with a breast on her thigh. He was dissecting fly eyes and brains; she was dissecting human eyes and brains. They could talk about their work for hours over a Friday-night dinner of sushi, squid, or cervelles de veau en matelote. Seymour would tell Carol about the bizarre mutant fly he had found that week, and Carol would say, “That sounds like the patient I saw yesterday.”

  Seymour and Carol got married, and in the early 1980s they embarked on a joint research project. In his Fly Room, one of his postdocs, Shinobu Fujita, had been taking bits of fly brains and injecting them into a mouse, just as if he were vaccinating the mouse against measles or chicken pox. The mouse would make antibodies against the foreign fly proteins. Then Fujita would clone those antibodies one by one, make a big batch of each, and use it to stain fly brains. With these monoclonal antibodies, as they are called, the Benzer group could stain the fly eye and brain with exquisite specificity. That is, each antibody attached itself to a specific fly protein or to a specific lump or angle of one protein and no other.

  Benzer watched the eye grow as if it were the lattices of a living crystal. A single fly eye has eight hundred hexagonal facets. (Illustrations credit 14.1)

  For their joint project, Carol and Seymour decided to test these antibodies on samples of the human central nervous system. Since antibodies are so specific, Seymour thought it unlikely that they would stain anything human. But it was a whimsical adventure to start their marriage: a marriage of true minds, as Carol told her friends. She took postmortem samples from four young human patients, cutting little blocks of about one cubic centimeter each from the spinal cord, optic nerve, hippocampus, cerebellum, lymph node, and liver. She deep-froze these blocks and prepared them in much the same way that Seymour had prepared his flies, shaving each frozen block very fine to make a series of microscope slides and applying the antibodies to each slide, one by one. If her patients had proteins or bits of proteins that were exactly like flies’ proteins, the stain would light them up in bright green.

  When Carol looked through her microscope, she was startled to see bright green on slide after slide. Almost half of the antibodies stained her human specimens. She found hit after hit. She and Seymour sat together in her laboratory, looking at the slides and shaking their heads. In effect, the antibodies had scanned the fly brain and the human brain and found dozens of identical molecular building blocks, which implied dozens of identical gene sequences. When Benzer had opened his Fly Room, he had hoped that the fly might have something to say about human genes and behavior, at least by way of analogy. But he had never dreamed that the fly brain and the human brain would turn out to have this much molecular machinery in common.

  Carol was just as surprised. The family likenesses were odd. One of Seymour’s antibodies stained just a small and specific portion of the retina in the human eye and the equivalent portion of the retina in the eye of the fly. Another antibody stained only the Purkinje cells in the middle layer of the cerebellum. Purkinje cells are the most spectacularly dendritic trees in the human brain. Each Purkinje cell has so many tiny branches and twigs that it makes 150,000 contacts with nerves around it. In other words, a single one of these cells makes about as many contacts in the human brain as a fly has brain cells. Many neurobiologists believe that this prodigious branching of connections produces the human brain’s unprecedented power. Biologists who hate sociobiology maintain that we can learn very little about human nature by studying the instincts of other animals because the powers conferred by interdigitating neurons like these lift us too far beyond the other animals for their instincts to illuminate ours. In Carol’s slides, however, Seymour’s antibodies circled each and every Purkinje cell with dotted lines like broken halos. So although our brains are fancier, they are made of the same stuff.

  For Carol the stains were a bonanza. She saw immediately that they would help her explore the human nervous system, both normal and pathological, in finer detail than before.

  For Seymour, sitting in Carol’s pathology lab surrounded by jars of gray-brown, half-dissected human brains and gray-white human eyeballs, the green stains meant something else. They meant that at the level of genes, the family resemblances between species at far distant reaches of the tree of life must be very close. His old mutants might turn out to be more interesting than he had thought.

  A marriage of true minds. When Seymour Benzer met the neuropathologist Carol Miller, they began discovering uncanny connections between the genes of flies and human beings. Here, Carol holds a human brain in her laboratory at the University of Southern California School of Medicine, in Los Angeles. (Illustrations credit 14.2)

  THE UNIVERSAL FAMILY likeness of genes was soon confirmed again and again around the world as the first sequence data began to come in and were published in computerized databases. Biologists typing in a search for a string of genetic code they had just sequenced in a fly found hits in the ox, the goat, the sculpin, and the mushroom. It was a moment of huge collective simultaneous discovery. There has never been anything quite like it in the history of science. Tens of thousands of genes or gene sequences in human beings turned out to have close counterparts in the fly, the worm, the yeast, the mustard weed, and even E. coli. The discovery would have thrilled Darwin, although it was an old truth for poets. George Herbert wrote in “Man,” “Herbes gladly cure our flesh; because that they/Find their acquaintance there.”

  The news caused at least as much excitement on Wall Street as it did in the academies. In Cambridge, England, where the double helix had been discovered at midcentury, molecular biologists founded the company Hexagen to look for clues to human diseases in the genes of the mouse. In Cambridge, Massachusetts, molecular biologists founded NemaPharm to look at the genes of the worm and Exelexis to look at the fly. The chief drosophilist at Exelexis explained to investors recently that it is astonishing how much one can learn from flies at the level of the genes: until the mapping projects began, he said, drosophilists had never realized “that we were looking at little people with wings.”

  This was one of the great developments of late-twentieth-century biology. It means that every biologist studying every genome can now feel more or less at home in all the rest. And Seymour cherishes a sentimental feeling for the way he and Carol got their private preview of the family likenesses in the tree of life.

  To this day, Carol and the pathologists in her laboratory are using Seymour’s antibodies to explore neurodegenerative diseases of the human brain, such as Alzheimer’s, Huntington’s chorea, Parkinson’s, and amyotrophic lateral sclerosis (Lou Gehrig’s disease), a disease her mother developed. Carol and Seymour cared for her in their home in San Marino. The disease killed her mother, but Carol kept tissue samples and blood samples for her research program. Carol’s strongest interest was in Alzheimer’s disease, and she found abnormalities in vulnerable neurons that no one had ever described. Today Seymour’s fly strains are helping Carol untangle the tangle of Alzheimer’s by tracing precisely what goes wrong in the populations and subpopulations of cells that Alzheimer’s slowly blights.

  Meanwhile in Benzer’s laboratory his Korean postdoc Kyung-Tai Min is screening fly mutants, searching for brain degeneration patterns that literally look like human ones. That is, Tai is trying to find fly brains and human brains whose problems look alike by visual inspection. First, he screens for mutant flies with reduced life spans. Then he dissects their brains and examines them with an electron microscope. He is finding all kinds of distinctive lesions in the flies’ brains that look remarkably like the lesions in the textbooks that Carol has lent him from her pathology lab: pictures of brains with Alzheimer’s, Parkinson’s, Lou Gehrig’s disease, Huntington’s. When Tai finds a parti
cularly interesting case, in which both the symptoms and the brain stains are alike, Seymour tells Carol about the case over dinner before he goes back to the lab.

  His old hero Arrowsmith also remarried—though not as happily. The front door of their house in San Marino has a stained-glass window they designed together in which fly brains and fly eyes are decoratively disguised as flowers. A framed reproduction of Vermeer’s Woman with a Turban hangs in the den.

  Sometimes Carol and Seymour arrive together at Seymour’s Sandwich Shop for lunch. While they eat, Seymour’s postdoc Tai shows them his photographs of fly brains. Then they name the latest fly mutants after the foods that the flies’ brain lesions remind them of: egg roll, popcorn, spongecake, bubblegum, meringue, chocolate chip.

  CHAPTER FIFTEEN

  The Lord’s Masterpiece

  The Gods are here, too.

  —HERACLITUS

  THE GENE period has a distinctive run of letters near the center, a run that repeats again and again: ACA GGT; ACA GGT; ACA GGT … This stretch of code produces a corresponding repeat of two amino acids in the period protein. There the repeat goes threonine-glycine; threonine-glycine; threonine-glycine; threonine-glycine; …

  After Bambos Kyriacou left the Drosophila Arms and set up his own Fly Room at the University of Leicester in England, he and his students began collecting melanogaster from points all around the compass and examining this run of repeats. They collected flies from Bristol, England; Leiden, the Netherlands; Bordeaux and Saint-Tropez, France; Casablanca, Morocco; Andros, Greece; Rethimnon, Crete. Back in the laboratory, they sequenced period gene after gene. They found that not all of the strains had the same number of repeats: some had seventeen pairs, others twenty, others twenty-three. The farther from the equator, the longer the run; the colder the fly the longer the run.