The knot of our condition was twisted and turned in that abyss.
—BLAISE PASCAL,
Pensées
BENZER KEEPS a clipping file of genes-and-behavior headlines so that as they are discredited he can use them in his lectures as cautionary tales. In the three decades between 1965 and 1995, studies were announced—often with great fanfare—linking human genes and violence, reading disabilities, manic depression, psychosis, alcoholism, autism, drug addiction, gambling addiction, attention deficit disorder, posttraumatic stress disorder, and Tourette’s syndrome. Every one of these studies had to be retracted.
Today, with the tools of molecular biology growing more sophisticated and the maps of the human genome filling in, Benzer thinks it is possible to do good work at last. Skeptics like Lewontin say the good work will never come, that this whole field will be remembered someday with the same contempt we now lavish on Galton’s eugenics. But Benzer thinks that thousands of solid links between genes and human behavior will be discovered over the next several decades. He is eager to read these stories, and like everyone else he is particularly hungry for information about the traits that have shaped his own life. He thinks he is probably a clock mutant, and in the middle of the night he sometimes marvels at the gift that this one mutation has given him, a lifetime of solitude in the laboratory. Human clock genes are now being cloned, sequenced, injected into the eggs of mice, and dissected by the techniques that Benzer and his students pioneered in the fly.
Benzer also wonders if he is a thermostat mutant. His lab coat, shirt, and sweater do not always keep him warm in Church Hall, although everyone else in his lab wears T-shirts. These extra layers are not a sign of age; they are a sign of Benzer. “My fingers are cold,” he has told people all his life. “Feel them. I’m ten degrees off everybody else.” Even forty years ago, camping in the desert with Dotty and the Delbrücks, Benzer wore two sweaters, two pairs of pajamas, and something around his neck. Dawns in the desert were a daily double whammy because they were so cold and so early. The Delbrück family had a saying: “More tired than Seymour at the Grand Canyon.” Whatever the cause of it—probably poor circulation—it is a single brush stroke that has shaped his life. One reason Benzer works at Caltech and not at Harvard, which has made and lost five bids for him over the years, is his dislike of snow.
This is the way we define ourselves. We single out a few traits from all the tens of thousands, a few traits that vary a great deal from everyone else’s, and we watch their effects at the choice points the way Benzer does with his flies. At Benzer’s seventieth birthday party, Francis Crick told a few stories about a sabbatical year Benzer spent with him at Cambridge in the late 1950s. Crick and Benzer sat in the same tower room at the Cavendish Laboratory where Crick and Watson had discovered the double helix, fiddling with the same rods and cutout pieces of tin with which Watson and Crick had built the first model. “We gradually got used to Seymour’s habits,” Crick remembered at the birthday party. “Not getting in too early …” Benzer always claims Crick’s tower was drafty, but Crick says, “Well …” No one else in the lab ever noticed any drafts. “We surmised, by sort of inspection, that Seymour was wearing more than one sweater, probably two or three, I think. And I have heard that on occasion he even wears two pairs of socks. Seymour,” Crick announced, enjoying himself, “I’ve come to the conclusion, for reasons that I’ll mention later—perhaps in your style of work—that you must have a very low metabolic rate, and this accounts for what might be called both the exo-insulation and the endo-insulation.”
That was an insult worthy of a genius. Crick was implying that a single genetic flaw explains four of Benzer’s most colorful traits: one, his outer layers; two, his inner layers (because there have been years when Benzer has cast a round shadow even without the sweaters); three, his late hour of rising; and four, his wittily simple experiments. Crick likes to hint that all four of these traits of Benzer’s derive from just one defect: Benzer is lazy to the core, and he invents his cut-to-the-chase experiments out of sheer indolence. This is Crick’s favorite dig at Benzer. It is the way he describes Benzer in his memoirs: “always one to avoid unnecessary work.” But then this is also Benzer’s favorite dig at Crick. Benzer simply can’t understand how everyone in Crick’s laboratory spent the morning drinking coffee, the afternoon drinking tea, and then got called to Stockholm for a Nobel Prize. “I don’t know,” Benzer said at his birthday party, parrying Crick, “it wasn’t clear at all when they did their work. At Easter vacation, all the gas was turned off in the laboratories. And at night, to get in, you had to wake up the concierge to let you in through the gate. So I still don’t quite understand that miracle.”
Because of his eccentric thermostat, Benzer took a personal interest in the work of one of his recent postdocs, Omer Sayeed, from Pakistan, who looked for thermostat mutants by putting flies in a clear plastic tube that sat on an aluminum slab. One end of the slab was hot, and the other end was cold. Wild-type flies always chose the middle of the slab, around 24° C. That seemed to be their Pasadena. Sayeed tried raising flies in a hot room and in a cold room, but when he gave them the chance the flies still chose Pasadena. The preference is innate, and that fascinates Benzer.
Sayeed also used the slab to test some of Benzer’s classic mutants, including one of the very first eccentrics that Benzer discovered in his countercurrent experiment, SB-8 (meaning Seymour Benzer’s Eighth), a mutant fly that does not go to the light. SB-8 turned out to be a thermostat mutant too. It did not prefer any particular piece of real estate on Sayeed’s slab, even if he made the slab icy at one end and infernal at the other. The fly seems to be thermo-blind. Sayeed and Benzer have renamed it bizarre.
DEAN HAMER, at the National Institutes of Health, is the most prominent molecular biologist to enter the field that Benzer pioneered, and to look at human beings. Hamer is gay, and in his first study of genes and behavior in the early 1990s he decided to study why some human beings are attracted to members of the same sex, while most human beings are attracted to members of the opposite sex. Hamer thought of this as a relatively clear-cut and dramatic behavioral variation with which to start his study, just as Benzer started by studying flies that turn away from light and Jeff Hall started by studying male flies that court other males.
Of course, it is harder to study a man’s choices than a fly’s. How much of the difference in sexual orientation between two American men is imposed by the way they see themselves and the way they try to behave in their culture? There are still many psychologists who argue that human sexual orientation is determined more by culture than by biology, more by nurture than by nature, which is less of an issue with fruitless. As a young lawyer, Abraham Lincoln shared a bed for two years with a roommate in Springfield, Illinois. Historians now argue about what that meant and whether Lincoln was homosexual. In The Invention of Heterosexuality, one American historian (also gay) argues that the very idea that most men are attracted to women and most women to men is a social invention.
But Hamer feels it is reasonable to assume that much of the difference is inborn. Many psychologists agree, and many gay men describe that as their subjective experience, in the tones of the Roman poet Horace: “Drive out nature with a pitchfork, she’ll always come back.” Or Voltaire: “We perfect, we smoothe down, we hide what nature has placed in us, but we put nothing there ourselves.” Twin studies in the early 1990s showed that among nonidentical twins, if one is gay the chance of the other being gay as well is about 25 percent. But with identical twins, if one is gay the chance of the other being gay is 50 percent. These findings suggest that genes help to shape the variation in sexual preference. At the same time, if one identical twin is gay, there is a 50 percent chance the other will be straight, so it is also clear that genes do not decide sexual orientation the way white and fruitless decide eye color and sexual habits in flies. The neuroanatomist Simon LeVay (also gay) believes he has found anatomical differences in the brains of gay and straight men. Although his findings and their implications are controversial, LeVay has reported differences in the hypothalamus, differences as marked as those that other investigators have found there in men and women.
Hamer recruited study subjects through outpatient HIV clinics and gay men’s organizations in Washington. He took blood samples from each of his volunteers and administered various personality tests. He also did a standard pedigree study of each volunteer, looking for homosexual relatives in each family tree. Hamer was intrigued to see that the gay men in his study were more likely to have gay uncles and gay cousins on their mother’s side than their father’s. Every biologist since Morgan would know what that suggested: that there might be a link between the trait and the X chromosome. Since a man has only one X chromosome and he gets it from his mother, any trait linked to the X will pass down through the mother’s side of the family.
If a gene on the X chromosome makes a man more likely to be homosexual, two homosexual brothers should be likely to share that gene and also some of the genes around it. This is the same mapping principle that Sturtevant hit upon in Morgan’s Fly Room. Hamer checked a series of twenty-two markers that span the X chromosome. By now he had his choice of computer programs to crunch the numbers for him (he used LINKAGE 5.1). The program pointed to a link between the homosexuals in his group and a marker at the far end of the long arm of the X, at a site called Xq28.
From his data, Hamer could not tell what the gene might be, how many male homosexuals in the population at large might carry the allele at Xq28, or what portion of their sexual orientation was influenced by that allele. Hamer could say only that somewhere within about four million base pairs on the tip of the long arm of the X chromosome there might be a gene that might somehow relate to the sexual orientation of the men in his particular study. In other words, compared to the kind of work that had been done for decades with flies, the finding was tentative, and, being a careful molecular biologist, Hamer presented the finding to his colleagues that way.
But genes, behavior, and homosexuality are such charged subjects that Hamer’s story caused a national sensation. Within days of the announcement, many gay men were buying a T-shirt in gay bookstores: “Xq28—Thanks for the genes, Mom.” At the same time, gay activists denounced the work; they were afraid that the suggestion that homosexuality is in the genes might someday lead another Hitler to attempt another Final Solution, or lead millions of parents to use a prenatal diagnostic kit. The “gay gene” story provoked furious controversy both in the press and in the scientific establishment. A young postdoc in Hamer’s laboratory who had helped map the gene to Xq28 accused Hamer of picking and choosing which of his data to report. This was a serious charge. Hamer’s colleagues at NIH began a confidential inquiry, and so did the Office of Research Integrity in the Department of Health and Human Services. After news of the ethics investigation broke in the Chicago Tribune, Hamer sent a note to Science by e-mail defending himself and saying that he doubted there would be so much controversy if he were working on any topic other than homosexuality. He was cleared in 1996, and all charges were dropped. Meanwhile, a study in Canada found no evidence of the linkage that Hamer had seen—not even a link to the X chromosome, much less the tip of the long arm of the X chromosome. But that study was never published.
In the middle of these storms, Hamer enjoyed hearing about a discovery by two colleagues at NIH, Ward Odenwald and Shang-Ding Zhang. They were looking at the development of the fly’s nervous system, studying a gene called pollux (which acts in concert with a gene called castor). To find out what pollux does, they had made a DNA transformation cocktail with pollux and a heat-shock promoter, so that the gene would turn on only when they turned up the heat. All this was standard procedure by now. Also following standard procedure, they used the early embryo of a white-eyed fly and added the normal allele of the gene white to the DNA transformation cocktail, so that they could see at a glance which flies came out of their eggs transformed. A fly that popped out with red eyes would carry the gene pollux. When Odenwald and Zhang watched these flies in a warm room, they were surprised to see the male flies begin dancing around and around in circles on the walls of the fly bottles.
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 people 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 eggs, 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.
A computer operator from the south of France goes back to his ancestral village in Ethiopia. His family left Africa years before he was born. But when he meets his grandfather, who is the chief of the village of Shembe, three hundred miles from Addis Ababa, he sees that they not only look alike, they look at the world alike and move through the world alike. After the computer operator goes home to France, he learns that his grandfather has changed his will and named him the next chief of Shembe.
A teacher from Texas goes back to his ancestral village in Scotland. His grandparents are dead, but he sits down to tea with a great-aunt. He offers to pour, and as he tips the pot his great-aunt gives a little cry: “Oh, my God, your granny! It’s in your hands!”
A mother calls a therapist to talk about her son. The boy has just turned fifteen, and he is acting as loutish as his father, a man she threw out of the house a little more than fifteen years ago, a man the boy has hardly met. Does she have a gift for turning men into louts, or is her son his father coming back?
A mother in Manhattan watches her son’s face as he sleeps. She left his father in Paris soon after the boy was born. Her son hardly knows him. But more and more often, even when he is dreaming on his pillow, she seems to see in his face expressions that remind her of his father, expressions that seem to her impossibly, indefinably French.
All these anecdotes point in the same direction as the celebrated studies of identical twins raised apart, including the twins who are both gunsmith hobbyists; the twins who are both raconteurs; the twins who are both hysterical gigglers; the twins who can enter the water at the beach only by backing up, timidly, “and then only up to their knees.” Of course, there are anecdotes that point in the opposite direction: the young girl who looks and acts like neither of her parents; the adopted boy who grows up to walk, talk, think, and laugh exactly like his adopted father.
“I think genes and behavior are such a headline item,” Benzer says, thinking of his clipping file: GENE DISCOVERED FOR BEDWETTING. GENE TIED TO LOVE OF NEW THRILLS. “But the trouble is, when you go look at the data, they are often really fragmentary.” He sees dubious measurements and marginal correlations. “Much as I believe in genes and behavior, the idea has caught on too much. It’s become an idea of complete destiny. I think that’s wrong. Genes are not always expressed. Even if you work with fruit flies, you see that genes are not always expressed.” We each carry many genes we never express. The likelihood that we will express a gene we carry is called the gene’s penetrance. Penetrance is not the same for each gene. “Look at the bible,” says Benzer—meaning the drosophilist’s bible, The Genome of Drosophila Melanogaster, a book that lists every fruit-fly gene ever found since white, and rates the penetrance of thousands of them. “You can have a gene with ten percent penetrance, or five percent, or one percent. So just having that gene doesn’t mean you’ll show that phenotype. Expression depends on a myriad of chemical reactions. And that’s not generally understood. People think if you have the gene, your fate is sealed.”
Benzer is sure that when the picture of genes and behavior begins to fill in, there will be no such thing as “the gay gene” or “the curiosity gene” or “the happiness gene.” All these traits will prove to be at least as complicated as a fly’s tendency to move toward light—and Benzer now knows hundreds of genes that affect that single trait. Students of genes and behavior will dissect vast complexes and constellations of genes that work together, as in the clockwork in the fly.
But as the science he helped to start comes closer and closer to home, he sees patterns and questions everywhere. He visits his grandson at his high school during lunch break, and he thinks: What a field for study. His grandson says that every lunch break, the same students stay inside and the same students go outside. Outside, there are the students who lean on the cars, the students who sit around by the bikes, and the ones by the flagpole. Each group has its own attitudes and makes its own moves at the choice points. Benzer is sure that behind these choice points and behind all the schoolhouse culture that surrounds them, there must be a thousand and one differences in the genes. The choices may be too complicated to dissect at the moment, but the influence of the genes is real and ever present. “It’s not random,” he says. “None of it is random.”
He daydreams now in the middle of the night about simple traits that one might dissect soon. Sometimes he remembers Galton’s old idea about the instinctive dread of blood. Benzer once had a graduate student who was an extreme case. He would faint at the sight of blood, even the mention of it. He passed out once at the Faculty Club, and once at Benzer’s house, too. People would forget themselves as they stood around talking shop and munching adventurous hors d’oeuvres in the living room, and there he would go again. “Try to catch him! A real phenomenon.”
Then there is the drinking question. When Benzer watched his crews of postdocs back in the bacchanalian sixties and seventies, he used to remember an old Yiddish song from Brooklyn. A Jew goes into a bar, he drinks a thimbleful of wine. A goy goes into a bar, he drinks a barrelful of wine. And the chorus:
Drunk he is
drink he must
because he is a goy—
Hey!
Jeff Hall, who is half Irish, likes to make an ironical toast when he hoists another brown bottle at midnight: “Those Irish alleles!”
The next generation of molecular biologists is trying to study those choices now, and there are signs that this trait, complex as it is, may be illuminated by studies of genes. Lee Silver of Princeton University is another molecular biologist of Hamer’s generation who is moving into the study of genes and behavior, and alcoholism is one of the traits that Silver is studying now. He works with mice, and he finds the current possibilities for research in murine genes and behavior so exciting that he often wishes he could extricate himself from every other project in his lab and do nothing else.
Of course, for studies of behavior as complicated as alcoholism, a mouse makes a somewhat problematic model, as Silver himself points out. A mouse will never say, “Gee, I’d like another drink, but I guess I shouldn’t.” A mouse will just take that drink. On the other hand, this too makes the mouse useful: all those layers of willpower, experience, education, and nurture do not come into play. In fact, looking for links between genes and behavior is so straightforward with mice that Silver lets his undergraduates do most of the work. Not long ago, one of them designed an experiment in which she offered inbred strains of mice two spigots, one for water and one for alcohol (10 percent ethanol, about as strong as Chardonnay). An inbred mouse strain known as C57BL/6 will drink three quarters or more of its liquid from the alcohol spigot. A second inbred strain, DBA/2, will drink almost none—less than one hundredth of its liquid diet will come from the alcohol spigot. A DBA/2 mouse drinks so little alcohol that it is likely to take no more than a single small taste from the sipper tube and never go back.
A senior of Silver’s, Justine Jaggard, crossed these alcoholic mice and teetotaler mice. Then she crossed the children with teetotalers. Some of the grandchildren drank a great deal of alcohol. Some drank almost none. Jaggard tested the DNA of the mice for a large number of markers that she knew to differ in the alcoholic and the teetotaler strains. Now she could see which of these markers were most often found in the alcoholic mice. Those markers had to lie next to or near to the genes that made the difference in their behavior.
One night in June, just before the end of her senior year, Jaggard found a locus on mouse chromosome 2 that seemed to predispose male mice to alcoholism, and a locus on chromosome 11 that seemed to predispose female mice to alcoholism. The gene in the female mice seemed to account for roughly a fifth of the variance in their drinking patterns. She called Silver first thing the next day: “I got an awesome result last night at three o’clock in the morning. I know. I can’t believe this actually worked. I’m so excited. Hooh! But anyway. Well, it’s real! I’m totally, totally excited. But there’s no mistake!”
Today students of Silver’s are crossing aggressive and passive strains of mice; mice that are subject to seizures when they hear loud and high-pitched noises and mice that are immune to those same noises; mice that are monogamous and mice that are polygamous. With each of these traits Silver expects to begin finding complexes of interacting genes and dissecting those complexes, while he looks for corresponding genes in human beings. He also has a graduate student who is making mouse mosaics to help trace the fine-grained differences of their behavior to their brains. They will engineer a mouse so that half its cells are male and half are female: random bits and blotches of maleness and femaleness, from the fur to the brain. Then they will test these mice and see how their behavior varies, depending on which part of the brain inherits which genes. “It’s a fantastic idea we came up with together,” Silver says. “We get this from Drosophila gynandromorphs. Conceptually, it’s the same thing: genetic dissection as opposed to surgical dissection.”
Like most biologists in this exploding field, Silver speaks enthusiastically of the genetic dissection of behavior without thinking of the source of the phrase. “A lot of this comes from Seymour Benzer’s vision,” Silver acknowledges. “In the back of my mind, that’s where it’s coming from, even if we don’t express it. He was the one. And from that vision it just goes on everywhere.”