Time, Love , Memory

by Jonathan Weiner

  “This sounds almost like whining, but it isn’t.” Hall preferred problems that no one else cared about. It would have cost him his soul to jockey with the journeymen in the field of nerve growth. “That’s so solid,” he used to tell people. “It’s blood and guts. Whereas behavior just seems this vast, open-ended chaos. In other areas you can just fight your way through with more work, and you get through the molecular or anatomical problems you face. But with behavior, half the time it just seems we’re just floundering and we don’t know how the hell to cope with it. So it’s not a complaint at all. I don’t work on behavior and feel an outcast.” Hall felt like an outcast, so he worked on behavior.

  Benzer hated the new crowds too. His laboratory’s work on the growth of fly embryos, fly nerves, and in particular fly eyes had made the fly eye one of the hottest fields in neurobiology. “And there was enormous competition between Seymour’s lab and Gerry Rubin’s lab in Berkeley,” recalls Michael Ashburner. “That’s probably passed now, because they’ve each moved on. But at one time they were both doing rather similar experiments and certainly following a rather similar strategy, and I think there’s no question that Gerry’s lab did it more successfully than Seymour’s—that the tension of that competition wasn’t helpful. This is just an anecdote. But I was at Berkeley in ’84, ’85, can’t remember now. And I remember going down to Caltech. Fifteen or sixteen people sat around in Seymour’s coffee room, had sandwiches, and chewed the cud for kind of an hour and a half. And eventually Seymour said, ‘Well, back to work, chaps.’ And I said, ‘Well, I’ve done my bit for Gerry Rubin.’ He was, ‘What do you mean?’ I said, ‘Well, I’ve kept all your lab off the bench for the last hour and a half, didn’t I?’ ”Ashburner cackles. “He turned absolutely white. He didn’t think it was funny at all. It was true, of course.”

  Now Konopka’s gene period was no longer an object of merely eccentric or philosophical or human curiosity. Such a gene had to be connected in some unknown but intricate way with the living machinery of the fly. So period became a model for the way nested cogwheels of genes work together to produce behavior, and more fundamentally as a model for the way genes work and for the way to figure out how genes work. Serious science and money were riding on these questions. The two principal molecular biologists among the clock watchers, Rosbash and Young, each won grants from the Howard Hughes Medical Institute guaranteeing their laboratories funding of $1 million per year. Hall did not win a Hughes. “I’m a pseudo-molecular biologist,” he says, “a pseudo-crypto–molecular biologist. I’m really more of a geneticist.” He had always been closer to Morgan’s tradition, and now he felt more an outcast than ever. Konopka was in even worse shape: he had failed to get tenure even at Clarkson.

  With the new tools of molecular biology, the standard order of business is cloning and sequencing. Molecular biologists clone a gene, make billions of copies of it, chop the gene into bits, and find out how the gene is spelled—for instance, GCTAAAT … —the same routine to which the robots of the Human Genome Project are dedicated. To find out what a given gene’s sequence means, molecular biologists can then alter its spelling one letter at a time, changing a G into an A or an A into a C. They can clone each of these variant genes, insert each variant into a fly embryo, and watch to see how each change in spelling changes the gene’s behavior. By cloning a gene from a human being and inserting it into a fly, a worm, or a mouse, or by changing the spelling of a fly gene and reinserting it into a fly, molecular biologists can get clues about the nature of the gene.

  In this way, every week, another old and unanswerable question becomes answerable. Recently a team cloned and sequenced a gene that makes Mendel’s peas wrinkled or smooth. The difference lies in a tiny fragment of DNA in the middle of the gene, a little block of letters that has jumped into the gene: the kind of jumping gene that McClintock studied in maize. These jumping genes are now known as “transposons.” This particular transposon is stuck in the pea gene like the proverbial lost wrench in the engine. If a pea plant inherits a version of the gene that has the transposon stuck in it, the plant cannot make a certain enzyme, starch-branching enzyme I. Without that enzyme, the plant cannot make a certain protein, branched-chain amylopectin. Without branched-chain amylopectin, the pea plant’s cells tend to fill up with abnormal amounts of sugar. The peas swell. When they dry out, they wrinkle.

  Molecular biologists have also cloned and sequenced a gene that makes Mendel’s pea plants tall or short. That gene codes for an enzyme that manufactures some of the building blocks of a plant hormone known as GA1. GA1 is a gibberellin, a growth hormone. One version of this gene makes an enzyme that manufactures the building blocks with a single amino acid misspelled. Because of that single misspelling, the pea plant produces only one twentieth the normal quantity of growth hormone, so the plant grows up short.

  By the late 1980s, in principle, anyone who wanted to know why white has white eyes could now find out. Anyone who wanted to understand the workings of the strange genes that Benzer and his raiders had discovered could find out. The original mutants had been novelties, and it had been extremely difficult and probably impossible to work out the function of many of them simply from the classical genetic analysis that Benzer and his students had done in his Fly Room. Merely mapping the genes to their chromosomes, as Benzer and his crew had done, using the tools of classical genetics, would never have told them how the genes work. To understand that, they had to find out what protein each gene makes. Then they had to track that protein through the body and see what the protein did. Even today that kind of search can be difficult, but in the early days of Benzer’s Fly Room it was impossible.

  IN 1986—once again in a dead heat—the rival clock laboratories in Boston and New York determined the complete sequence of letters in the period gene. The portion of DNA that encodes the period protein is a length of approximately 3,600 letters of genetic code. No one had ever sequenced a gene that shapes behavior. Now that they had the sequence in front of them, the neurogeneticists could see exactly what is different about period zero, the first mutant that Konopka had put on the map, the mutant with zero sense of time. The mutation that makes its behavior so eccentric is located in the first half of the period gene, which is now known familiarly as per. At nucleotide 1390, counting from the start of the coding sequence, the letter C has changed to the letter T. This point mutation transforms the three-letter word CAG (which means “glutamine”) into the three-letter word TAG (which means “stop”). So when a fly cell comes to that TAG, the cells production of period protein stops. At that point the cell is close to finished with its production. It has already transcribed its period DNA into period RNA. Ribonucleic acid (RNA) is the compound that carries genetic messages from the DNA inside the cell’s nucleus to the protein-building machinery outside the nucleus. But the cell’s translation of period RNA hits that stop about one third of the way through its production of the protein, and the fly can never finish the job. Over and over the fly manufactures that same useless fragment, like a worker on an assembly line who has received a torn sheet of instructions.

  The clock watchers could also see what is wrong with the code of Konopka’s per short and per long, the mutants with clocks that run five hours faster and five hours slower than normal. In per short, at nucleotide number 1766, the letter G has changed to the letter A. In per long, at nucleotide number 734, the letter T has changed to the letter A. These changes do not break the clock, they only accelerate or decelerate the hands. Again a point mutation, the smallest possible mutation, makes the difference, producing short days or long days for the fly, just as the change of one letter of code gives short stems or tall stems to peas.

  Hall, Rosbash, Young, and their teams were now in an unprecedented position to trace the mechanical connections between a gene sequence and a piece of behavior. They had opened the back of the clock, and now they could try to feel their way through the mechanism from gene to metabolism to behavior—which had been Benzer’s ori
ginal goal for the work when he had founded the field. For this enterprise a clockwork gene was the perfect place to start. The internal workings of the system could safely be assumed to be extremely regular. And variations in the behavior stood out clearly because the behavior they were studying runs like clockwork too. “Some fly behaviors are just chaos,” Hall says, “hopelessly irreproducible, a total mess. But rhythms are not that way.” So the clock gene made an ideal model, a perfect point of entry into the connection between genes and behavior.

  Now that they had cloned and sequenced the gene and discovered that spurious stop, they translated the rest of the code, triplet by triplet, which told them every amino acid building block in the period protein. They had hoped that finding the protein would lead them straight into the clockworks. But Hall, Rosbash, and Young soon discovered that in spite of all they had learned so far, they were still stymied because they had no idea what the period protein actually did in the fly; nothing quite like it had ever been seen before.

  “Because we are at the beginning of something, we don’t know what is going to emerge,” Rosbash used to say stoically. “It’s like a garden in spring. Very early spring. You know, like, winter.” It was a long, cruel season of search and blunder. For several years they struggled with no forward motion. All of the principal investigators suffered errors of judgment that make them blush now (“Partly a function of hysterical racing, of racing other people to get the answer,” says Rosbash). For a time they thought the period gene might be involved in the way certain cells in the brain communicate with one another; they thought the period protein might work in the gap junctions between nerves to set rhythmic pulses flowing through the brain. And for a time they thought the period protein was a proteoglycan, which is a protein as brambly, tangled, and hard to work with as a thornbush in a bog.

  “This phase of the story, from ’85 to ’87, was the low ebb of work on this or any other gene,” Jeff Hall says today. He, Rosbash, Young, and Kyriacou often felt as if they were stuck in a sand trap in the middle of an hourglass. “And outsiders said the same thing,” Hall remembers. “ ‘You guys make all these crazy findings and claims, and they don’t seem to make any sense. What is true? What is going on here? Does anything make sense? Are any of the simple data of any validity?’ ”

  It was the archetypal project of the new biology. Where the first decades of the century merely mapped gene to trait, they were trying to go into the clockwork and trace it all the way from the gene to the movement of the hands on the clock. The rival clock labs were finding out just how difficult that is; and they were not alone. Elsewhere, progress in the study of hundreds of other genes was also agonizingly slow. Having found the approximate location of a gene on the map of the chromosomes, investigators thought they would soon be able to clone it, sequence it, and find out what it does. Then they would have the first clues to the causes of diseases and the way to treatment. That research model was the source of the power, money, and people flooding into molecular biology. Investors thought finding genes was everything. They were encouraged in that belief by able propagandists such as Watson, who told Time magazine in 1989, “We used to think our fate was in the stars. Now we know, in large measure, our fate is in our genes.” Like Francis Galton before them, the leaders of the field sometimes spoke now as if the next sunrise could banish what the ancients had understood so well: the twists, turns, and depths of human nature. The dreams they dreamed or encouraged others to dream showed an insufficient respect for the complexities of human unhappiness and for the depths of physiology that lie between gene and behavior. Meanwhile, down in the trenches, molecular biologists were beginning to understand that even after they found, mapped, cloned, and sequenced a gene, their search had only begun. They still could not do anything with the gene until they knew what the gene does. Every gene is a thread that leads into vast skeins of molecular anatomy, and one by one molecular biologists have discovered how easy it is to get lost at the very beginning of the thread. There is so much they do not know.

  Konopka put the period gene on the map in 1971; Hall and his friends and rivals sequenced it in 1986 and 1987; and even in the early 1990s, no one had a clue how the clock worked. Drosophilists and drosophilosophers gossiped about the period problem in Fly Rooms around the world: “Ah, yes, per. The gene that promised so much and never quite delivered.”

  CHAPTER FOURTEEN

  Singed Wings

  Philosophy is really Homesickness; the wish to be everywhere at home.

  —NOVALIS

  E. O. WILSON had published his famous book Sociobiology: The New Synthesis in 1975. There he analyzed the social instincts that bring together colonies of ants and bees, herds of wildebeests and antelope, tribes of chimpanzees, pairs of flies. In the last chapter he turned to human beings and argued that we are instinctively social animals too.

  That fall, the molecular biologist Jonathan Beckwith, the population geneticist Richard Lewontin, and other colleagues of Wilson’s denounced sociobiology in highly publicized attacks. They argued that Wilson could not make this leap; that although the rest of the animal kingdom is shaped by instincts, the human animal has gotten free of the slavery of instincts and works largely by different rules, the rules of culture. It was the nature-versus-nurture argument of the first half of the twentieth century in its most concentrated form. Wilson was vilified by bullhorn in Harvard Square, his classes were leafleted and picketed, and there were times when he was afraid he would be physically attacked by demonstrators, although the worst that ever happened was when a woman at a scientific meeting in Washington dumped a bucket of ice water over his head while protesters from a group called the International Committee Against Racism chanted, “Wilson, you’re all wet.”

  “I had unexpectedly—unexpectedly to me, anyway—stumbled into a hornet’s nest of resentments and fears that represented, to some extent, a holdover from the activist period of the sixties,” Wilson says now. “When I got into this controversy, I realized early on that I had both a challenge and a responsibility to explore the subject further.” So Wilson did more thinking and reading in 1975, ’76, and ’77, and wrote the book On Human Nature, which won the 1979 Pulitzer Prize. There he explored some of the earliest work on the language instinct, homosexuality, and other topics in human behavior genetics, and tried to interweave the science with philosophical and ethical considerations. Today many of his case studies seem dated and speculative, but the book’s basic argument is straightforward. When we look at ourselves against the background of the other animals, we can begin to see that we, like they, have distinctive traits. These traits most resemble those of our nearest living relatives, the chimpanzees. These facts support the hypothesis that we are shaped by our genes; they contradict the hypothesis that we have escaped our genes. It is hard now to appreciate the heat that this thesis could engender at that time and in that place. “It’s died down a great deal since the late seventies,” Wilson says. “It was worth your head to discuss these subjects too openly in the seventies.”

  In the 1970s, Benzer and his school were studying genes and behavior too, and they were studying the subject from the one angle of attack through which knowledge becomes power. But they worked so far outside the hot glare of lights that lit and singed Wilson that histories of the controversy do not even include Benzer in their indexes. He never attracted Wilson’s enemies, partly because he never wrote a book. He was also apolitical, like his mentor Delbrück before him. On the day of his Nobel Prize ceremony, in 1969, Delbrück had written in his diary that he was depressed: “The main reason for my depression is my feeling guilty. All the time one is questioned about items one doesn’t know anything about, though one should. These questions refer to a world outside the ivory tower which I used to ignore successfully.”

  The outside world ignored Benzer successfully. Yet if any research program in biology deserved to be watched, his did. He and his students were dissecting genes that are central to animal behavior: points of entry in
to time, love, memory. “But that took a while to prove,” says one of Benzer’s students’ students, Ralph Greenspan, who now runs a Fly Room at the Neurosciences Institute in San Diego. “And between the time when you report and the time when you prove …” Until quite recently there were grounds for skepticism. Benzer and his students were also protected from serious attention by their laboratory animal. Today Benzer sometimes exclaims when he sees a headline, “We were doing that thirty years ago! The fly is always regarded as kind of an abstraction.”

  In a quiet way, the molecular biologists were doing work that would eventually help to vindicate Wilson and some of the aims of sociobiology, long after the subject had been so raked over and tarnished that virtually everyone in the field had abandoned Wilson’s name for it. “Wilson always hated the molecular biologists,” says one of his colleagues at Harvard’s Museum of Comparative Zoology. “And yet they’re the ones who won his war.”

  The war did singe Benzer too, just as he was turning away from behavior. In 1979, he was asked to deliver a lecture about genes, learning, and memory at a plenary session of the Sixteenth International Ethological Conference in Vancouver. That September, a few weeks after the lecture, he received by certified mail a six-page, single-spaced letter attacking his work. The same letter appeared in the mailboxes of the entire Caltech faculty and all of the invitees of the Vancouver conference.