Time, Love , Memory

by Jonathan Weiner

  After a year’s study, Odenwald and Zhang decided that the gene that had made the difference for the flies was white, the gene that started modern genetics. They could make fruit flies chain just by injecting the normal allele of white into the eggs and turning up the heat. They even speculated in their paper that their gene might turn out to be a clue to homosexual behavior in human beings, which was a naive leap; and again the story attracted national press attention. Time magazine ran the headline “Search for a Gay Gene,” with the headline wreathed in a circle of chaining male flies.

  The finding has since been replicated at Yale, but the basis for the effect remains unknown. Until it is explained, the leap from white to human beings is at best premature, as Jeff Hall explained at the time of the discovery to everyone within earshot. “It’s completely silly,” Hall told a reporter from Science News. “Nobody between now and doomsday will think white is going to have anything to do with behavior in mammals. The chance of this is one over the number of neutrons in the universe.”

  Of course, there is a lesson in white for human beings and for the human future. By now, white is one of” the best-known genes on earth. It is the gene that put genes on the map, the cornerstone of modern genetics. Drosophilists have now been working with it in Fly Rooms all over the planet for most of a century. And white is also the gene that started the whole century of talk of “a gene for.” It always seemed the simplest possible model of a gene linked with a trait. That such a gene can cause such complicated and unforeseen behavior when injected into a fly is a cautionary tale for those who may begin in the next few years to think about injecting genes into the eggs of human beings, even genes linked with apparently simple and innocuous traits like blond hair or blue eyes.

  This is why so many drosophilists stay away from the human stories. “I wouldn’t touch that one with a barge pole,” they tell one another when they see headlines about Hamer.

  “Flies have no political constituency.”

  “It’s a sobering thought,” Tully says, when he considers—as he must—that his work on creb may someday lead to attempts at genetic engineering, attempts on the human brain. For him the apolitical approach of the last generation is no longer possible, if it was ever tenable. For a molecular biologist of his generation the twentieth century teaches the impossibility of pure research. “What went through Einstein’s head when he saw E equals mc squared?” Tully asks. “ ‘Shit, we can blow up the planet’? Did he say that? I’d suspect in his dark hours he knew it would be abused. We have the same phenomenon here with this enhanced memory. We can see it now, and we know it’s real. And that really kind of brings in a new day.” The genetic dissection of behavior has concrete implications now that once seemed like science fiction. “Now it is science fact, like fission. There is a potential here for serious abuse.”

  Tully wonders what the military would do if it got hold of drugs for memory enhancement. “Think about it. A perfect drug for the CIA.” Send in agents, take a memory enhancement pill, the agents have brilliant memories during the operation—and then they lose it all afterward. “And then you weren’t there. Perfect. You know? Think about the pressure of a general who has thirty minutes to communicate a data-rich conversation of specifics of bombing missions to a group of pilots before going off to drop bombs. Do you think he’d cram, then take a memory enhancer? They’d be champing at the bit for drugs that could modulate memory in that fashion. And yet that’s not what we want them for. I’m a pacifist. I would hate to see this understanding perfected for the art of war, for all the covert and overt atrocities that humans push over on each other. But it’s possible. You could go science fiction. What would it be like if a child popped a memory enhancement pill every day before school? What would that child’s head be like after twelve years of education? What would the child accomplish with that store of information? That’s an interesting question to ponder. And would it even work? Can the brain deal with it? Is the capacity there to deal with what we’re imagining could be produced? We don’t know.”

  Tully thinks of clocks too: “Maybe arrhythmic mutants lead to depression. Take the drug, you cycle. Well, does that mean you could put it in the water supply of the Iraqis?” In other words, even an apolitical gene like period may lead to medicines and weapons. “Could it work? I don’t know. What would industry pay for a drug that could easily set and maintain the clock for swing shifts in the plant? Is that what we want to do?”

  One of the most fascinating applications of his work, he thinks, would be a drug to block memory of trauma. He could use the off switch as easily as the on switch and make an amnesia pill: “The perfect treatment. Cutting it off at its source.” That would be even better than erasing memory of trauma: preventing it from being written down in the first place. “That could be the first and maybe always the best outcome of what we’re doing. Improve conditions for those who experience some really bad, sad, powerful thing. So do ’em a favor and wipe it off. Then they won’t suffer from the memory of it.

  “Then again, I wake up in the middle of the night and say, ‘Yeah, but would I be who I am without suffering?’ That’s a tough one. Thank God I don’t have to answer it. I just play with flies.”

  This is why Benzer is just as happy to study the eye of the fly instead of the behavior of the fly and to set the world of politics at a distance. It is a choice that fits the cricket-in-a-cage approach to science that he learned from Delbrück and his generation. For Morgan and most of his Raiders too, it would have been undignified and inappropriate to get involved in campaigning against health fairs and eugenics programs. To follow pure science was the Arrowsmith ideal.

  So Benzer follows his curiosity wherever it leads inside the fly. To an outsider that might sound confining. But to a drosophilist today the scope is infinite. As the century closes, there are six thousand drosophilists around the world, and their number is growing by 20 or 30 percent every year. Flies have turned out to be far more like us than anyone imagined in the 1960s, when Benzer (shocking his friends) turned back to the fly. Faster and faster, drosophilists add genes to their Web site FlyBase. The naming continues to be more whimsical and irreverent than physicists’ names for new elements, which tend toward the monumentally serious. FlyBase includes descriptions of all of the latest genes. In this way, drosophilists are continuing another tradition that Morgan and his Raiders started: sharing information as they get it, and not hoarding it as many other students of genes do. A recent story in the New York Times about the return of the fly (“NOW PLAYING AT A NEARBY LAB: ‘REVENGE OF THE FLY PEOPLE’ ”) began with a list of just a few of the stranger names: “Godzilla, genitalless, gut feeling, gouty legs, goliath, gooseberry distal, ghost, glisten, gang-of-three.”

  “Every single biological phenomenon on the face of the Earth or in the universe is studied now in Drosophila,” says Jeff Hall. “We’re not drosophilists anymore, we’re biologists who happen to use Drosophila. I mean, Drosophila meetings now are a joke. They’re about every aspect of biology under the sun.”

  Hall is still angry that his old boss Benzer ranges so widely in the fly—while neglecting behavior. “Benzer is an antidetective,” Hall says. “He doesn’t ever figure out anything. He’s not interested. Once problems get intense”—once a crowd of people converge on them—“he loses interest and drops them and starts looking for new things. In fact, if you look at the array of subjects on which he continues to publish, one sees an explorer who is rattling around the biological landscape like a superball!”

  IN JANUARY 1996, Hamer got a call from Israel. A team of molecular geneticists there was doing a study they thought might interest him. They had taken blood samples from a group of subjects and administered a personality questionnaire designed to measure four domains of temperament: novelty seeking, harm avoidance, reward dependence, and persistence, four traits that seem to a number of psychologists and behavior geneticists to be partly inherited. The novelty-seeking scale of the questionnaire tries to sort peo
ple into those who are more “impulsive, exploratory, fickle, excitable, quick-tempered and extravagant” and those who are more “reflective, rigid, loyal, stoic, slow-tempered and frugal.” The Israeli investigators found that those who scored higher than average in novelty seeking were also more likely than average to carry a certain variant form of the gene for one of their dopamine receptors.

  Dopamine receptors are famous in psychopharmacology because they are primary targets for drugs that are used to treat many neurological diseases, including Parkinson’s and schizophrenia. Pharmacologists and psychiatrists often prescribe a drug called clozapine for schizophrenics who have not responded well to other treatments. Clozapine binds with peculiar affinity to one particular dopamine receptor, D4. The repeats in the D4 dopamine receptor can lead to differences in its affinity with drugs, at least in laboratory tests. The gene is expressed in the frontal cortex, midbrain, amygdala, and medulla of monkeys, parts of the brain that are linked with cognition and emotional behavior. Amphetamines, cocaine, and alcohol are thought to change our mood by altering dopamine levels; so do antipsychotic drugs such as clozapine or haloperidol.

  The gene for D4 is on the short arm of chromosome 11, and the gene contains repeats. In some of us a run of forty-eight base pairs within this gene is repeated twofold; in some, fourfold; in others, sevenfold.

  While the Israeli team was studying the DNA of their volunteers in the Negev desert, behavior geneticists in England and in Boulder, Colorado, looked at what behavior geneticists working with mice call “emotionality,” or sometimes “reactivity.” When a mouse is placed in an apparatus they call an “open field”—a brightly lit white circular arena, a sort of spotlit stage—one mouse will spend most of its time exploring the stage, while another will spend most of its time keeping very still and defecating. The mice also behave in character when they find themselves in the dark arms of a Y maze. Their behavior can be predicted from their lineage. The investigators crossed mice that explored the stage with mice that fled the stage, tested their grandchildren, and looked at the DNA of the most extreme mice at each end of the scale. Then they entered all the genetic data in a computer program called MAPMAKER and found at least three loci, on murine chromosomes 1, 12, and 15, that seemed to be linked to a mouse’s emotionality.

  In the Israeli sample, most subjects had either four or seven repeats. The higher the subjects’ ratings in novelty seeking, the more likely they were to have the sevenfold repeat. So Hamer and some of his colleagues at NIH tested the blood samples they had already collected in their study of what has become known as the “gay gene,” together with other samples they collected from local college students. Then they re-sorted their subjects into two groups. One group had short alleles with two to five repeats; the other group had long alleles with six to eight repeats. When they checked the personality tests, they found that the long group scored higher on warmth, excitement seeking, and positive emotions. The long group also scored lower on conscientiousness; specifically, on a facet of conscientiousness that the test makers called deliberation.

  In Church Hall, Benzer combed through these new studies with the same mixed curiosity and asperity with which he had looked over Hamer’s claims for Xq28. Benzer has always felt that his own key trait is curiosity. In the hall outside his workroom, he keeps six spring-loaded steel file drawers full of maps: of Paris, Cambridge, Delbrück’s deserts, everywhere Benzer has ever been and hopes to explore again (“I don’t know, am I going too far? A map is a wonderful thing.”). In the same mood he now spends whole nights trolling the World Wide Web for its bizarreries. But he has added Hamer’s novelty-seeking story, which has not yet been solidly confirmed, to his clipping file. He thinks the finding may hold up, but again it has been absurdly overblown in the press. He mistrusts those multiple-choice personality questionnaires (“I think they’re scandalous”) and he suspects that the gene is a smaller beginning than the media hooplah suggested. According to one recent twin study, novelty seeking is about 40 percent heritable. By Hamer’s calculations, the dopamine-4 receptor gene accounts for about a tenth of that. At best the D4 gene would account for about 4 percent of the trait. So why call it “the novelty gene”?

  But in poetic if not in scientific terms, the name does have appeal, as the lead of the front-page story in the New York Times observed: “Maybe it is appropriate that the first gene that scientists have found linked to an ordinary human personality trait is a gene involved in the search for new things.”

  LATE IN 1996, Dean Hamer and another group of investigators announced that they had found a link between a human gene and the pursuit of happiness. This time they focused on a gene that codes for a protein that helps nerve cells to recycle the neurotransmitter serotonin. In human beings a certain transporter of serotonin, 5-HTT, is expressed by a single gene on chromosome 17. Hamer and his collaborators found a variation of the gene’s coding region about one thousand base pairs upstream, in a place that controls the gene’s transcription. There are repeats in the DNA here, and again most people in their sample fall into one of two groups: a group with a short form of the gene and a group with a long form.

  Hamer found that in his sample of volunteers those who had two copies of the short form of the gene scored higher in neuroticism than those who had two copies of the long form. The variation in the gene showed no significant connection to variations in the other personality characteristics: extroversion, openness, conscientiousness, and agreeableness. And as with dopamine, there is strong reason to believe that serotonin has a strong effect on mood and temperament. Drugs that inhibit the uptake of serotonin are often prescribed in the treatment of anxiety and depression. Changes in the transmission of serotonin cause anxiety in both animals and human beings.

  Again Benzer and his students were skeptical and waited to see if the findings would be replicated. But the press and Hamer himself greeted the discovery ebulliently. When Hamer’s computer program first found the link, he told his friends, “We found a happiness gene!—I shouldn’t call it that.” The day the study came out, he was quoted on the front page of the Philadelphia Inquirer: “Everybody will be happier.”

  Again the overinterpreting and overreporting in the press made the fly people and the mouse people glad they were staying with the fly and the mouse. Those come close enough to home. One brown mouse gives birth to a litter of pups. She nurses them, and she herds them back into her nest when they stray. Another virtually identical brown mouse gives birth to a virtually identical litter. But she never nurses them. She lets the pups wander farther and farther from her nest in the cedar shavings at the bottom of the cage, and almost all of them die.

  One white mouse snuggles for hours with the other mice in its cage, trimming their whiskers and letting them trim his. Another virtually identical mouse keeps to itself at the far side of the cage. Its bed in the cedar shavings is unmade and unfluffed, and its whiskers are untrimmed.

  One maggot, when it crawls to a crumb, always takes one or two bites and crawls on to the next crumb. Another virtually identical fruit fly maggot arrives at a crumb, settles down, and eats every bit before moving on toward the next crumb.

  The difference between the first mouse and the second, the mother superior and the mother inferior, is that one of them has a normal set of mouse genes and the other is missing a gene called fosB. The difference between the well-trimmed mouse and the unkempt mouse is that the second mouse has a problem in a gene called disheveled. The difference between the roving maggot and the sitting maggot is a single letter of genetic code in a fruit fly gene called foraging, also known as dgk2, at map position 24A3–C5 on the left arm of the second chromosome.

  The laboratories that engineered the mice are at Harvard Medical School and the U.S. National Human Genome Research Institute in Washington. The laboratories that created the roving and sitting maggots are in the open air, because this is a natural variation. Roving and sitting maggots are found wherever fruit fly larvae wriggle out of fruit fly e
ggs, which is virtually every temperate spot on the planet. Every fruit fly has to creep on the face of the earth for a few days as a maggot before it can metamorphose and take to the air. Apparently, among maggots both rovers and sitters are viable personality types.

  Every human being also has a copy of the mouse gene disheveled, the gene that is damaged in that unbarbered and unsocial mouse. Every fruit fly has a copy of disheveled too. In fact, like so many thousands of genes that now interest biologists, disheveled was first discovered in fruit flies. Drosophilists named it disheveled because a fly with a disordered form of that particular gene always pops out of the egg with his chest hairs in disarray.

  Portrait of a maggot, in a scanning electron micrograph. Some fruit-fly maggots are rovers, nibbling here and there and moving on; other maggots are sitters, eating every bite before moving on. The difference between the rover and the sitter is a single letter of genetic code in a gene called foraging. (Illustrations credit 18.1)

  WE LOOK AROUND the family table and see some fragments of behavior that seem to come out of nowhere, other fragments that we recognize instantly. Often it is ourselves we recognize. We catch glimpses of the way we chew or talk, laugh or frown, right down to the way we pour from a pot or sip from a cup. The secret faces of our inner lives glance back at us from the fracturing ripples of the gene pool. We also catch glimpses of ourselves in the faces of our animals, as if they, too, are reflected in the same wavering pool. These resemblances will fascinate the last human generation as they fascinated the first.