Time, Love , Memory

by Jonathan Weiner

  The natural sciences have now traveled up from the subatomic particles to the macromolecules, Wilson says, and are beginning to enable us to piece together the cell. We are now facing two great questions: “Question number one: ‘Is there any reason to doubt that the same thing can be done for whole organisms and for behavior, even complex behavior?’ In my opinion, no, there’s no reason to doubt it. The natural sciences have just had an unbroken series of successes doing this. Why should we doubt that we can go on? It may be vastly more difficult, but can it be done? Yes.

  “Second question: ’Can it be done from the top down?” Is there a possibility that major discoveries in mathematics or social theory will allow us to attack the whole subject from the top down, he asks, “and guide the reductionistic and experimental research safely home to harbor? Now I’ll give you another opinion: ‘No.’ I belong to the school that holds that it’s gotta be done from the bottom up and that what we need to do is just keep plugging away. These are the exciting areas of research. There have to be Seymour Benzers moving on up into human behavioral genetics, courageously. And as this occurs, then, I think, we’re going to see revealed to us principles that will make human behavior and the human mind more comprehensible in ways not yet imaginable. But it has to be done by hard slogging, as they say in the old black spiritual, ‘up the rough side of the mountain.’ And frankly, that’s the kind of—you know, I’m a dirty-fingernail biologist. That’s the kind of work I love.”

  BENZER HIMSELF avoids grand pronouncements. Generations of his students used to smirk with him at a yellowing book advertisement that was taped to the wall in Seymour’s Sandwich Shop: “Taking a purely phenomenological approach, Berger examines several closely related concepts: the Second Law of Thermodynamics, organic evolution, ontogenesis, learning, reinforcement, homeostasis, perception, will, consciousness, dreaming, and the Collective Unconscious.”

  If Benzer ever wrote a book, he would not go on like that poor overreaching Berger. He has always been daring as an experimenter but conservative as a theorizer. Years ago, while sending Delbrück a revised rII paper, “a more subdued draft of the rII story” (“It suffers,” he wrote cautiously, “from not quite answering any of the $64 questions.”), he kibitzed with his mentor about a paper by a newcomer to the phage work. “I had the feeling that he might be squeezing the data a little too hard, and was a little sad at the ‘cocktailizing’ of theories,” Benzer wrote in his letter. “Is it going to get as bad as nuclear physics?”

  By now, in Benzer’s opinion, the cocktailizing of theories in the study of genes and behavior has gotten much worse than it ever was in nuclear physics. Nevertheless, he is sure of the significance of the genetic dissection of behavior. “Psychology is going to be changed,” he says mildly but flatly. In his view the transition will be gradual, as the old guard dies off. “Max Planck said scientists never change. Scientists die and new ones come in. You see that around you all the time. And the very field that is now old hat may ten years down the line get rediscovered. Just like my old mutants.

  “I think there may be a tendency that fields change faster now,” Benzer says. “New fields are invented more rapidly than the generations turn over. So you automatically have an old guard, a very heavy background of old guard at any one time. I can see molecular biology getting old guard. I can see industry taking over. Molecular biology is going the way chemistry went thirty or forty years ago—hard-core industrial work. Subjects kill themselves off by their success. You say they are successful, but they are no longer at it. They are thriving but not at the cutting edge of intellectual advance. A student can take a course, train to fit in, it’s a discipline like every other. Adventurous minds look for somewhere else to go.

  “Always academies,” Benzer says. “Always the Beaux Arts screaming about the Impressionists and the Impressionists about the Modernists. And the Modern on the Abstract and the Abstract on the Postmodern, and the Post-Post. It’s the Feynman thing.” One generation sets a question aside, temporarily; and when a new generation comes along, takes it up, and does something with it, the old guard is appalled.

  Benzer himself has mixed feelings as he watches the next generation begin what he postponed, approaching human behavior and personality through the genes. But in one way or another he has been working toward this moment and preparing the way toward it through the fly for the last thirty years. He is electrified that now we can begin to see the connections in ourselves, just as we have seen them in the flies. Not long after he and Carol got married, he began asking friends if they wanted to see a snapshot of his new baby boy. The snapshot in his wallet showed twenty-three pairs of human chromosomes. Benzer would mock his own paternal pride by hamming it up as he pointed out the X and the Y. “That’s Carol’s,” he would say, “and this is mine. At least Carol says this is mine.…” He still finds excuses to show their son’s chromosomes at meetings when he talks about the genes-and-behavior stories that are now filling the news.

  His friends laugh. “Only a geneticist.”

  CHAPTER EIGHTEEN

  The Knot of Our Condition

  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 f
irst 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 Tr
ibune, 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.