A SINGLE DROSOPHILA is not much bigger than an asterisk. It is so small that an escapee from a fly bottle (the flies are always escaping, always in orbit around the four comers of every Fly Room) does not even buzz—unless it flies into a drosophilist’s ear. They seem silent without a microphone and they look like nothing without a microscope. But even in Benzer’s first nights among his first half-pint milk bottles, he felt that fruit flies might turn out to be a magic well.
When he placed a dozen of them in an upside-down watch glass, covered the watch glass with a piece of glass for a ceiling, and observed them at low power, at twenty or thirty times life size, the flies groomed and preened, each head twisting from side to side between the forelegs, each head “all eyes.” They rubbed their forelegs together in the inverted dome of the watch glass with a scheming “Ah-hah” look. When two or three met, he could see little flickering exchanges of the forelegs. The flies wandered around the watch glass, finding the very edges, and there preening again, the way a sheep will browse grass at the edge of a fence or a mouse will scratch its head at each dead end in a maze. Sometimes a fly would poke a few of its legs partway over the wall of the watch glass into the outer air and rest there, nine tenths a prisoner and one tenth free. Then, with a sudden—to human eyes instantaneous—rearrangement of parts, the fly was gone, off to another square centimeter inside the dome, exploring space and other flies.
Gradually more and more flies would cluster around the edges of the watch glass. Through the microscope the cuticles of their exoskeletons were brown but shiny, like armor. Light caught the neat red facets in the domes of their eyes. Here and there, Benzer saw a proboscis mumble its bristles against the inner walls of the glass like a baby elephant’s trunk, in and out, flashing and then withdrawn. Again and again the shiny wings bent, flexing backward and downward with the movements of the hind legs. At twenty- or thirty-power magnification, every bristle on every fly’s head stood out, sharp and countable—and Benzer knew that Drosophila had meant so much to thousands of geneticists that every bristle on the fly’s head had in fact been counted and given a name.
Seeing all this action, it was easy to hope that the lessons he wanted might come out of this small theater. The flies were as quick and deft as birds and almost as expressive. When they rubbed their forelegs together, they had, to human eyes, an attitude of scheming or of prayer; and when they rubbed their wings with their hind legs, they gave an impression of agility, expertise. The neatness and deftness of their behavior matched the neatness and deftness of their bodies, both sculpted by natural selection and both intricately and invisibly linked.
A human head could grow dizzy trying to go from the flies’ universe to ours, so unutterably distinct and so uncomfortably alike. Sometimes one of the flies would slip from the ceiling of the glass dome and fall flailing on its back in a panic of legs: awful to see, panic at thirty power, mildly contagious even across the gulf of the microscope.
Flies were as easy to play with as phage. “The work can be done almost pretty well anywhere,” as Morgan used to say, “so long as we have a table, and an electric bulb.” For Benzer, the chores were lightened because Ed Lewis already ran a spotless Fly Kitchen on another floor of the building. Working in the middle of the night, a team of lab assistants mixed fresh batches of yeast and molasses to order in a fifty-gallon vat, glopped measured amounts of fly food into the bottoms of freshly autoclaved milk bottles and test tubes, and wheeled warm, rattling racks of glassware to Lewis’s and Benzer’s labs every morning for their next rounds of experiments. Lewis’s former technician Evelyn Eichenberger taught Benzer how to knock flies out with ether so he could examine them under the microscope without letting too many of them escape. She also set up the standard morgues in the Fly Room: traditionally beer or wine bottles with funnels in their mouths and oil at the bottom. Any flies that did escape eventually found their way down the funnels and drowned in the oil. Each morgue slowly filled with sedimentary layers of mutant flies.
Sitting in the half-dark, Benzer sent mutagenized flies by the hundreds jitterbugging through his first countercurrent machine. From almost the first runs he noticed a few individuals here and there that stood out from the crowd in one way or another. Some of the flies did not move right along—they trudged so slowly that they looked depressed. While most of the flies around them made it all the way to Tube Six, these flies moped from One to Two. Benzer collected them by sucking them up one by one with a plastic straw (guarded at the top by a piece of fine mesh) and transferring each one to a bottle of its own. When he and his technician bred those flies, many of their children and grandchildren acted the same way.
Here and there in the countercurrent machine, Benzer saw a fly go into what looked like an epileptic seizure when he rapped the machine on the benchtop. He bred those flies, and some of their children acted the same way too.
He also noticed a few flies that seemed to march right through the countercurrent machine whether the light was ahead of them or behind them. Benzer bred those flies, and once again many of their children and grandchildren acted the same way. He wondered if these flies could see the light at all, and he asked one of the first postdoctoral students in his Fly Room, Yoshiki Hotta, who had just graduated from the medical school of the University of Tokyo, to check their eyes.
After considerable work, using a microscopic electrode, Hotta managed to record signals from the tiny nerves that run between the mutant fly eye and brain. As Benzer had suspected, the electrode’s readings, the electroretinograms, were abnormal. One of the first mutant flies that Hotta tested this way was tan, which has a light tan body and light tan antennae, and was first discovered in one of Morgan’s milk bottles. The tan fly was half-blind.
Benzer also built a flight tester. It was a 500-milliliter graduated glass cylinder with its walls coated on the inside with paraffin oil. He and Hotta put flies in at the top. Each animal, as it fell into the cylinder, would try to fly off horizontally. Those that flew strongly would get stuck in the oil near the top of the cylinder; those that flew more weakly would get stuck lower down. Those that could not fly at all would plunk to the bottom of the cylinder. The design was pure Benzer: simple and to the point. When he and Hotta collected flies from the bottom of the flight tester they found mutants that could not fly, just as in the countercurrent machine they found mutants that could not see. Together they dissected these flightless mutants under the microscope and found congenital defects in the flies’ wing muscles.
To Benzer, all these blind eyes and mangled wings were a proof of concept. But to the skeptics upstairs in the Sperry lab, they proved nothing. What did Benzer expect to find if he poisoned a fly? A sick fly. What could he learn from a sick fly? Sigmund Freud used to get the same reaction: “And you claim that you have discovered this ‘common foundation’ of mental life, which has been overlooked by every psychologist, from observations on sick people?”
Even Hotta sometimes worried that their research was way out. “When I decided to go to Seymour’s lab, nobody said, ‘Oh, that’s a very nice idea,’ ” he says. His advisers at the University of Tokyo had heard of Benzer’s adventures in rII; but not many of them liked the sound of his fly genes–and–behavior project. Packing for America, Hotta had told his professors, his friends, his family, and himself that he was willing to gamble: “ ‘It’s OK, I may be able to find something, may not.’ But I didn’t care. Of course,” Hotta adds now, “I probably cared.”
Delbrück, down in the basement of Church Hall, was feeling doubts about his own research. By now he had spent fifteen years on and off with his fungus Phycomyces, trying to understand something basic about the way the stalks tilt toward light—trying to see how to go from molecules to the senses. Delbrück and his students would mutagenize spores and let them grow with a light shining underneath them. Normal fungus would grow down over the rim of the agar plate toward the light. But here and there a mutant would grow straight up. Students down in the subbasement of Church Hall named the mutants that rejected the light mad in honor of Max.
As a laboratory organism, unfortunately, Phycomyces was as inconvenient as phage and flies were convenient. The fungus was harder to breed and cross, and its repertoire of behavior was, of course, limited. Delbrück was always trying to attract other fungus watchers the way he had attracted phage watchers. Sometimes he envied ethologists like Konrad Lorenz, playing outside by ponds and riverbanks. Delbrück wrote to his friend George Beadle, who was studying the genetics of another fungus, that he was “trying all kinds of things, from lunatic fringes to sober photochemistry.… Perhaps I should train a duck to follow me around, that sounds like a very appealing way of life.”
THERE WAS NO NAME for the science they were trying to start. It was not ethology, psychology, or behaviorism. It was not classical genetics, because classical geneticists like Morgan and his Raiders or Ed Lewis arranged their crosses and mapped their genes without reference to molecules. Nor was it behavior genetics, because behavior geneticists also bred animals without studying the underlying molecules. It was not traditional neurobiology, the study of the workings of nerves and brains; Sperry and his students were neurobiologists, and they were less than impressed. Benzer did not think that what he was doing was molecular biology, either, because his prime interest was animal behavior. An atomic theory of behavior was new science. Since it is a research program that moves from gene to nerve and from nerve to behavior, it is sometimes called neurogenetics. Given its deep roots in the natural sciences, it might also be called natural psychology. “I don’t care what you call it,” Benzer says. “I’ve often said, I don’t care about disciplines, I care about nondisciplines. What do you care about names?”
In 1967 Benzer published his first paper on the new work, “Behavioral Mutants of Drosophila Isolated by Countercurrent Distribution,” a paper that scientists in several disciplines now think of as a landmark. He was forty-six. He left Purdue, joined the biology department at Caltech, and moved into the laboratory space in Church Hall where he still works today.
Benzer had written that first paper as a kind of mission statement for his research program. But the project that proved the plan could actually work was done by a graduate student of Benzer’s, Ronald J. Konopka, from Dayton, Ohio. Konopka joined the laboratory because he wanted to use Benzer’s genetic scalpel to find and dissect the sense of time. He thought there must be a master clock hidden in the clockwork of life, and he thought Benzer’s method was the way to find it. Morning glories know when to bloom. Bears in caves know when to wake up. Grunions know when to spawn. (“And doubtless, when swallows come in the spring, they act like clocks,” says Descartes.) During the Enlightenment the French astronomer Jean-Jacques d’Ortous de Mairan performed a famous experiment with heliotrope, a plant whose Latin name means “turning toward the sun.” The heliotrope’s leaves and stems unfold every morning when the sun comes up and fold again every evening when the sun goes down. In the summer of 1729, the astronomer dug up a single heliotrope plant, brought it inside, put it in a pitch-black room, and peeked in every now and then. Even in the dark room the plant was raising its arms and lowering them again, keeping time with the heliotrope out in the garden. A note about this experiment appeared that year in the Histoire de l’Académie Royale des Sciences: “The sensitive plant follows the sun without being exposed to it in any way. This is reminiscent of that delicate perception by which invalids in their beds can tell the difference between day and night.”
The astronomer’s experiment inspired innumerable imitations. A French botanist carried “sensitive plants” down into a wine cave and watched them by candlelight—not a bad research project. A Swiss botanist tried growing sensitive plants in a room lit only by banks of lamps, and he managed to change the plants’ behavior by lighting or snuffing the lamps. The great Swedish naturalist Carolus Linnaeus dreamed of putting together a flower clock made of evening primrose, marigolds, childing pink, scarlet pimpernel, hawkbit, bindweed, nipple wort, passion flower, spotted cat’s ear, and the Star of Bethlehem, “by which,” Linnaeus wrote, “one could tell time, even in cloudy weather, as accurately as by a watch.” The passion flower would open at noon, the evening primrose at 6 p.m., and so on. One summer, Darwin drew a series of diagrams of a single leaf of Virginia tobacco as it stirred upward and downward from three in the afternoon to 8:10 the next morning.
Silverfish, crickets, spiders, scorpions, and squirrel monkeys have a sense of time. Biologists proved this by simple experiments, building exercise wheels like the wheel in a mouse cage and monitoring an animal’s cycles of sleeping and waking on the wheel in windowless rooms that were never dark or never light. Twentieth-century biologists built exercise wheels like these for sea hares, lizards, and cockroaches; and they built balances like seesaws so that every time the creature moved, it tilted the seesaw. The more they looked, the more they discovered that the sense of time is everywhere. Even single-celled animals such as Euglena have a sense of time. Euglena swims like an animal but has green chlorophyll like a plant. In a pond, each cell swims more by day than by night; at night it tends to sink sluggishly downward and downward through the water column. And even in a lab in constant light it keeps to this rhythmic cycle, which biologists call “circadian,” meaning “about a day.”
The literature on circadian rhythms is full of strange factoids about the sense of time in living things. The cells of a banana divide just after dawn. Some animals have clocks longer than twenty-four hours: a normal human clock, for example, runs a bit slow in a cave or a windowless room; we automatically adjust it every day to keep in time with the sun. Our clocks are reset by the dawn. The clocks of mice run a bit fast, and they are reset by the dusk. Confuse the sense of time of a homing pigeon—shift its clock six hours by tricking it with lights—and it will make a ninety-degree error in the path of its flight. Many people can order themselves to wake up at, say, seven in the morning—and they will wake up within a few minutes of seven. “All this showing,” as Spinoza says, “that the body itself can do many things from the laws of its own nature alone at which the mind belonging to that body is amazed.”
By the middle of the century most biologists assumed that this sense of time must be in the genes. But contrarians argued for nurture, not nature. Living things might learn to keep time with the beat of the sun the way goslings learn to follow Mother Goose or Konrad Lorenz. They argued that each seedling, gosling, and newborn baby might be imprinted by the sun, learning the rhythm of day and night and then keeping the beat, keeping time with the sun for the rest of their lives. Some biologists speculated that even sensitive plants sequestered in a wine cave might keep time by picking up subtle tides in atmospheric electricity or tides of cosmic rays, or perhaps secret signals linked to the phases of the moon, cycles of sunspots, or the rotation of the planet.
To prove that the sense of time is a matter of nurture, not nature, a biologist at Northwestern University, Frank A. Brown Jr., designed elaborate experiments involving carrots, seaweed, crabs, rats, and much solitude and darkness. He grew potato plugs in sealed jars and monitored the rhythms of their metabolism by sampling carbon dioxide and oxygen with gas detectors. He shipped oysters from New Haven, Connecticut, to his laboratory in Evanston, Illinois, and watched them open and close their shells rhythmically day after day in pans of seawater. In another herculean experiment he watched and timed 33,000 individual mud snails as they crawled out of holes. He also lobbied the U.S. National Aeronautics and Space Administration to put one of his potatoes into orbit. He wanted to see what would happen to its metabolic rhythms when the potato was aloft in a satellite and could no longer feel the rotation of the planet. NASA never took up his potatoes.
In 1960, a botanist tested Brown’s hypotheses in a cheaper experiment by flying Syrian golden hamsters, among other creatures, to the South Pole. There he put the hamsters and their cages on a turntable so that their rotation would counteract the rotation of the Earth. (The Earth’s rotation cannot be counteracted this way except at the pole.) The hamsters went right on waking and sleeping at the same times and with the same rhythms as hamsters that were not revolving on turntables. Apparently the hamsters did not need any cues from the rotation of the Earth to keep track of time. The botanist also put bean plants, fungi, cockroaches, and fruit flies on his turntables. All of them kept time perfectly.
After that experiment, it seemed clear to almost every biologist on the planet (except Brown) that living things really are born with some kind of inner clock. But no one knew where the clock might be hidden in the body or how it might work. One test of a true clock is its ability to keep time through a wide range of temperatures. A clock that speeds up in hot weather and slows down in cold weather is not a clock, although it may make a good thermometer. So a drosophilist checked the clock in fruit flies by raising them at different temperatures. Heat and cold did nothing to change their rhythms. Whatever they had inside them, wherever it was concealed, and however it worked, it really did deserve to be called a clock.
In 1969, at a meeting on the sense of time, the botanist who had gone to the South Pole, Karl Hamner of UCLA, declared that the problem was as mysterious as gravity before Newton: “What we need now is another Newton.”
MEANWHILE, Konopka was experimenting in Benzer’s laboratory. The behavior the flies are named for is waking up in the morning: Drosophila means “lover of dew.” In fact, the flies display their love of dew from the moment they are born. Each young fly develops inside a pupal case. When it is ready to emerge, the fly does not pip its shell with a beak, like a bird; instead it inflates a tiny balloon on its head, like a steering-wheel air bag, and bursts right out of the pupa. Benzer thinks a fly emerging from a pupa is one of the sweetest things in nature. The fly crawls out wet, like a newborn baby. Its wings are not yet inflated; they are crumpled like a new butterfly’s, and because of the air bag its head is still disproportionately large, again like a newborn baby’s. In nature, the flies usually emerge around dawn, when the world is moist and dewy. Even if a jar full of fly pupae is taken out of the light and placed in total darkness for several days, the young flies will still emerge together in the dark, around the time of their virtual dawn.
By the time Konopka went to work with Benzer, biologists had already mounted round-the-clock watches on fruit flies. They had discovered that normal flies live on a daily cycle just like the astronomer’s heliotrope. At sundown a normal fly becomes very quiet. It does not close its eyes, but it stops moving and looks as if it is asleep on its feet. At sunup it begins to move around again. Flies will keep to this daily cycle even in total darkness, just like the heliotrope.
In Benzer’s laboratory, Konopka poisoned flies with EMS to make random “typos” in their DNA. He used these poisoned flies to establish hundreds of separate lines of mutant flies. When he was finished, he had hundreds of fly bottles, and each bottle contained a separate line of mutants. Konopka spent most of the summer of ’68 watching these mutants’ children eclose in bottle after bottle, looking for flies that missed the dawn. It was a lonely way for a young man in California to spend the summer, and most of the professors and students who passed by his door thought he was wasting his time. The smart money said that Konopka had chosen a piece of behavior too central and too complicated to dissect through the genes. A mechanical clock has hundreds of gears, springs, screws, and ratchets. A living clock might require hundreds of working parts too, and hundreds of genes to make each part. But the parts of a clock are complexly interdependent, and if EMS caused a mutation in any one of those hundreds or thousands of genes, the result for the fly was likely to be a broken clock. That is to say, any of hundreds or thousands of mutations would have the identical effect on the fly, destroying its sense of time. So even if Konopka did find a clock mutant, he still might not have a clue what had gone wrong inside it. A fly without a clock might not even live long enough to eclose.
The ragging that Konopka endured that summer would later become a legend in the Benzer lab and far outside it. Geneticists and molecular biologists would tell the story to the tune of “They Laughed at Columbus.” “They said, ‘It’s too much work!’ ” says Jeff Hall, who was another of Benzer’s first postdoctoral students. “They said, ‘You’ll never find them!’ They said, ‘If you make one, it will die!’ But he told them, ‘Bugger off!’ ”
Konopka kept all of his flies at a constant temperature in cycles of twelve hours of white fluorescent light and twelve hours of darkness. For the sake of sanity and simplicity, he checked the bottles only twice a day: just after the lights went on in the morning, and just before the lights went off in the evening. If the flies had a normal sense of time, very few of them would eclose before that first check in the morning. When he inspected their bottle in the morning, it should still be full of eggs. The flies would eclose from those eggs in the next few hours of light, and he would find them creeping, crawling, and flitting around in the bottle when he checked on them that evening. So if Konopka checked one of his fly bottles first thing in the morning and found dozens of newborn flies inside it, he would know that they had eclosed sometime in the night, and he would suspect that there was something wrong with their sense of time.
In bottle after bottle, the flies behaved normally. But in the two hundredth bottle, when Konopka checked in the morning, he saw that it was teeming with flies. And when he inspected them one by one, he saw that most of them were males. Konopka bred those males. When it was almost time for their children to eclose, he put them into absolute darkness and waited to find out what they would do. Not many eclosed at dawn. They eclosed at all hours of the day and night, just like their fathers. He had found his first clock mutant.
In a second bottle, Konopka discovered a line of mutants that eclosed at the wrong time too. And when he mounted a careful watch over them he saw that they eclosed too early. Apparently their dawn came sooner than it came for the rest of the world. And in a third bottle he found a line of mutants that eclosed too late.
Konopka talked over the case of these three mutants during a long, meandering lunch with Benzer and Hotta and a few other students. They all wondered what the mutants’ sense of time would be like after they eclosed. Over lunch, Benzer thought of a quick way to help Konopka find out. As Benzer tells it now, this was another small countercurrent moment. “The people in the lab were split. One guy said, ‘That’ll never work. If that works, I’ll buy you an Indonesian dinner.’ ”
So Benzer tried it. He went back to a standard gadget from physics and chemistry, a spectrophotometer. The centerpiece of a spectrophotometer is a little glass square-sided cylinder called a cuvette. When physicists or chemists have a mystery substance to identify, they pour a few drops of it into the cuvette and switch on the spectrophotometer. The gadget fires a series of light beams through the cuvette: all the colors of the rainbow, plus ultraviolet and infrared. A sensor analyzes each beam as it passes through the cuvette, and a marking pen makes a series of squiggles on a rolling drum of paper. Sometimes the investigators can identify their mystery substance from the pattern of the squiggles on the paper.
Benzer put two strips of black tape on the outside of the cuvette, with a little space between them for the beam to pass through. Then he put one of Konopka’s flies inside the cuvette, and corked it with a cotton plug. He set the spectrophotometer to infrared, which flies can’t see. Whenever the fly moved from one end of the cuvette to the other it would pass between the two strips of tape and block the infrared beam, and that would make the pen jiggle up and down on the drum of paper. When he was finished, Benzer turned on the machine and let it run all night.
The next morning, Konopka arrived at the second floor of the Church Laboratory and found paper spewed out all over his floor in an almost endless scroll. He fished through loop after loop of paper and looked at the bursts of inky squiggles. The trick worked. He could see exactly how-busy the flies had been every minute of the night.
(“So that was a very good dinner, actually,” Benzer says. “J.J.’s Little Bali, near the airport, in Inglewood.”)
Later, Benzer’s postdoc Yoshiki Hotta built a whole set of gadgets based on the same principle, so that Konopka could monitor many flies at once. Now Konopka could find out what his mutants were doing in the dark. A few days of monitoring told him that his first line of mutants was consistent in its inconsistency. Not only did these mutants eclose at all hours of the day and night; for the rest of their lives they woke and slept, wandered and paused at all hours of the day and night. They acted like insomniacs. They seemed to be time-blind.
The line of mutants that eclosed early was also consistent. The day after they eclosed, they woke up about five hours too early; they did the same thing for the rest of their lives. Apparently these mutants did have clocks, but the clocks ran too fast. Their days had a period of nineteen hours. And Konopka’s third line of mutants, the line that eclosed late, was just as consistent. They woke up late every day of their lives. Their clocks ran slow. Their days had a period of twenty-nine hours.
Konopka examined the mutants through a microscope. All of them, females and males, throughout all the stages of their life cycles, from egg to larva to pupa to adult, looked absolutely normal. And when they bred, they passed on their sense of time from generation to generation. He could see that in bottle after bottle only the mutant flies had a warped sense of time.
If Konopka had been working with chicks, chameleons, monkeys, guinea pigs, potatoes, or heliotrope, he might not have been able to push this work any further. But with Drosophila the next step was obvious. He crossed his short-period mutants with a few classic mutants from the Fly Room, including white, singed, yellow, and miniature. Methodically, using cross after cross, he began trying to map the short-period mutation, using the same method that Sturtevant had invented in Morgan’s first Fly Room. The method was the same, but now he was trying to map a gene that was manifest not in the color of the fly’s eyes or the shape of its wings but in its behavior: a mutation that changed the way it moved through time.
Konopka found that the short-period mutation mapped to the far-left end of the X chromosome, less than one map unit from white. When he mapped the arrythmic mutation, he found that it too was on the far-left end of the X chromosome, also next to white. He mapped the long-period fly, and again it was on the far-left end of the X chromosome, also next to white.
By now geneticists called the map unit the centimorgan, in honor of the man who had started their science. If there is a 1 percent chance that two genes will be separated by crossing-over, those two genes are said to be separated by one centimorgan. Konopka’s three mutants were less than one centimorgan away from white, and they were zero centimorgans apart from each other.
Now Konopka was amazed. These were the first three time mutants he had found, and they all mapped to precisely the same place. Because they mapped to the same place, they had to be alleles, or variants, of the same gene, like tall and short in Mendel’s peas. Konopka had looked at more than two hundred strains of mutants to find these three time mutants, and all three of them pointed to the same spot on the same chromosome. He had barely started his search, and already he seemed to have stumbled straight into the center of the living clock.
By arranging marriages for his mutants, Konopka created flies that had one normal copy of the clock gene and one mutant copy. He also made flies that had two normal copies and flies that had two abnormal copies. It was just like breeding Mendel’s pea plants—tall-short, tall-tall, short-short—but this was behavior. He monitored the flies’ children and grandchildren, reading the scrolls of paper day after day. He could see that two of these mutations were at least partially recessive, like shortness in peas, white eyes in flies, or blue eyes in human beings. The short-period mutation was partially recessive. The mutation that destroyed a fly’s sense of time was also recessive. That is, if a fly inherited one broken copy of the gene and one normal copy, its sense of time was almost normal—its clock ran just half an hour slow.
In test after test, all three mutations mapped to the same spot. They were clearly alternative versions of the same gene. In the jargon of genetics, each spot on a chromosome is a locus. Konopka had discovered three alleles of a locus on the X chromosome that shapes the fly’s sense of time. He had now earned the right to name the gene. Because a change in the gene had the power to change the period of the fly’s days, Konopka called it the period locus.
He had found a very peculiar gene, and he had found it in his first two hundred bottles. Later on, when Benzer and his students, building on this first success, began to wander in many new directions, Konopka would formulate Konopka’s Law. It was his first law, and so far it is his only law: “If you don’t find it in the first two hundred, quit.”
WITH THE DISCOVERY of the clock gene, the sense of time, mysterious for so many centuries, was no longer a mystery that could be observed only from the outside. Now it could be explored as a mechanism from the inside. The discovery implied that behavior itself could now be charted and mapped as precisely as any other aspect of inheritance. Qualities that people had always thought of as somehow floating above the body, apart from the body, as if they belonged to the realm of the spirit and not of the flesh, as if they were supernatural, might be mapped right alongside qualities as mundane as eye pigment.
At the time, not many people at Caltech or elsewhere were prepared to believe Konopka’s mutants or his maps. They could not believe that his X marked the spot. “People really resisted the notion that this had anything to do with the phenomenon,” Konopka says now. “They could never get it through their heads what it meant that these mutations were all at the same locus.” Three different mutations in one locus meant that he had found not just a piece of the clock but a central piece, maybe the central piece, the pacemaker of the fly’s behavior, the piece of living machinery that keeps it waking and sleeping and moving in time with its planet from the moment it is born. His map suggested that a single gene can shape vast arrays of behavior, that individual genes can have extraordinary power to influence a life. He could even hope (though it was only a hope) that the gene he had found in the fly would tell him something about the mechanism that drives our own human sense of time.
As Konopka made more and more crosses and his map became more and more convincing, Benzer and Konopka got excited—but not the skeptics up and down the hall. “They would try to deny it,” Konopka says now. “They couldn’t think about it. They didn’t appreciate the power of genetics. They refused to believe that anyone would get the pacemaker.” Ever since the turn of the twentieth century, biologists had been trying to approach the mysterious center of life by way of genes. “But they would refuse to believe someone would have a handle on this.”
Not even Hotta trusted Konopka’s results. “I cooperated with him very heavily,” Hotta says now, “and I constructed the machines he used to assay the behavior. But at that time, I was rather skeptical about the gene, and so I dared not put my name in the paper.” Konopka and Benzer wrote up a report, “Clock Mutants of Drosophila melanogaster,” and sent it to the Proceedings of the National Academy of Sciences. At a party in Pasadena, Benzer told Delbrück that they had found alleles of a new gene linked to behavior. Benzer explained why he and Konopka thought the mutants had something wrong with their sense of time.
“I don’t believe a word of it!” Max Delbrück doubted the genes-and-behavior stories that began to pour out of the Benzer lab in the second half of the 1960s. Here, Seymour explains and Max doubts, after a seminar at Caltech. (Illustrations credit 8.1)
“I don’t believe it,” said Delbrück.
This scene also became part of the Konopka legend. Konopka was standing right next to Benzer and Delbrück at the time.
“But Max,” Benzer said, “we found the gene!”
“I don’t believe a word of it,” said Max.