Saturday, January 01, 2000

A Real-Life Arrowsmith Finds His Sinclair Lewis

Time, Love, Memory: A Great Biologist and His Quest for the Origins of Behavior

By: Samuel H. Barondes M.D.

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In the early 1960s, when I was just learning the tools of the trade of molecular biology, many of its founders were already looking for a new challenge. Flush with their success in solving the molecular basis of heredity, and concerned that their little field was beginning to get crowded, some began to dream about solving an even more formidable problem, the molecular basis of behavior. What seemed most interesting as a starting point was the inherited aspects of behavior, because it could be studied with tools with which they were already familiar.

I first got a wind of this trend in 1962, while working as a postdoctoral fellow in Marshall Nirenberg’s laboratory. Still in the midst of a race to decipher the genetic code—a race which would lead him to a share of a 1968 Nobel Prize—Nirenberg excitedly informed me that he was preparing himself for yet another scientific adventure by reading  Herbert Jennings’ 1906 classic, Behavior of the Lower Organisms, which describes the behavioral repertoire of unicellular creatures such as amoebae and paramecia. Nirenberg hoped that one of these creatures might prove to be an ideal subject for studying behavioral genetics.

In this, as in his work on the genetic code, Nirenberg was following the lead of other pioneers. Among them was Max Delbrück, a physicist who helped invent molecular biology by studying viruses that infect bacteria, called bacteriophage (or phage). By 1953, the year that James Watson and Francis Crick published the structure of DNA, Delbrück had already decided to abandon his ground-breaking work on bacteriophage and to search for genes that control the innate tendency of a fungus, Phycomyces, to grow toward light. Delbrück’s hope was that Phycomyces would do for behavioral genetics what phage had done for molecular biology.

Delbrück’s shift from bacteriophage to behavior was soon emulated by another leading phage geneticist, Seymour Benzer, the hero of Jonathan Weiner’s Time, Love, Memory. Benzer, like Delbrück, had a first, successful career in physics before switching to biology. He quickly made a big splash in his new field with a series of studies of a phage gene (called rII ) that provided a first glimpse into the details of gene structure. But Benzer, at age 40, was looking for a change; and he found himself becoming increasingly fascinated with the inherited features of human behavior. As Weiner tells it:

Benzer began to notice that whenever he read something about rII he felt bored, and whenever he read something about behavior and personality he felt alive. He was using what Crick calls the “gossip test.” Crick believes that “what you are really interested in you gossip about.” Benzer listened to his own gossip, his wife’s, and his friends’, and he felt the pull of the problem of genes and behavior.

Like Nirenberg and Delbrück, Benzer began searching for the optimal organism with which to study behavioral genetics. During a prolonged visit to the California Institute of Technology (Caltech) he became friends with Edward Lewis, who had spent his professional life working on genes that control the development of the fruit fly, Drosophila melanogaster. Lewis had trained with Alfred Sturtevant who, while a student of T.H. Morgan, invented gene mapping in the fly. Together these three had established a tradition of research on fruit flies at Caltech that Benzer found irresistible. Benzer decided to move to Caltech, and to work on the genetics of behavior in fruit flies. He would look for behavioral mutants and try to identify the genes that were responsible.

Time, Love, Memory describes some of the behavioral mutants that were identified by students and post-doctoral students in Benzer’s lab, and the structure and functions of the relevant genes. Weiner concentrates on mutants that affect three categories of behavior: daily behavioral rhythms (time); male courtship rituals (love); and the retention of learned experiences (memory). Descriptions of the work in each of the three categories focus on the activities of one of Benzer’s trainees. By following the careers of these younger (but now middle aged) scientists after their apprenticeship in Benzer’s laboratory, Weiner adds a rich topping of human interest to this delicious scientific pudding. 

KONOPKA’S BREAKTHROUGH

The work that put Benzer’s program in behavioral genetics on the map was done in collaboration with his student, Ronald Konopka, in the late 1960s, and published in 1971. It is a remarkable story that illustrates how genetics can sometimes make decisive contributions to analysis of a complex behavioral process, with implications far beyond anything that might have been hoped for. 

Konopka, who was interested in the innate 24-hour rhythms displayed by many organisms, came to Benzer’s lab with the ambitious (to many, at that time, impossibly ambitious) aim of identifying a fly gene that controlled these rhythms. His initial goal was to find a mutant fly with an abnormal daily rhythm. To search for such a mutant, Konopka took advantage of the observation that normal flies are always “born” (i.e. emerge from their pupal cases) at dawn, and that this is a reflection of the 24-hour rhythm that is already established before birth. 

To begin this search, he created a large number of mutants by poisoning their parents with a chemical that randomly damaged a few of the genes in their eggs and sperm. Eventually he was in a position to grow fertilized eggs of each mutant line (with mutations in one or more unknown genes) in a separate bottle so that he could observe the timing of their birth. By examining the bottles precisely at dawn (as set by a clock-controlled laboratory light) he could, in principle, detect mutants whose timing was off—assuming, of course, that such mutations could be generated, and that a fly that carried such a mutation would be viable. 

Amazingly, it worked. Konopka’s 200th bottle contained mutants with an irregular internal clock, some born before the dawn, and others born at various times thereafter. Even more amazing was Konopka’s subsequent discovery of still another mutant whose internal clock ran too fast, with a period of about 19 hours; and of yet another whose internal clock ran too slow, with a period of about 29 hours. Furthermore, all three categories of mutants were shown to be reflections of different variations in the structure of the exact same gene. 

To give you an idea of how unexpected this result was (I still remember my astonishment when I read about it almost 30 years ago), here is how Weiner describes Delbrück’s reaction to hearing this news: 

At a party in Pasadena, Benzer told Delbrück that they had found alleles of a new gene linked to behavior. Benzer explained why he and Konopka thought the mutants had something wrong with their sense of time. “I don’t believe it,” said Delbrück “But Max,” Benzer said, “we found the gene!” “I don’t believe a word of it,” said Max.

If you read Time, Love, Memory, you will come to believe every word of it, as Delbrück soon did. You will also learn a great deal more about this gene, named period, the subsequent identification of related genes in mammals (including humans) and the interaction of period with other fly genes that also play a role in 24-hour rhythms; and you will learn that there are genes (including period) that influence courtship and others (such as dunce) that influence memory. But even without these details, the main point should already be clear: some single genes play central and identifiable roles in complex behavioral patterns. 

THE BITTER WITH THE SWEET

Stories like Konopka’s discovery of period are what scientists like to remember and the public likes to hear. But the lives of scientists are also full of disappointments. While emphasizing scientific triumphs in Time, Love, Memory, Weiner does not neglect frustrations and failures. 

The career of Ronald Konopka provides a poignant example. Although he won a faculty position at Caltech on the basis of his exceptional discovery of the period mutants, Konopka failed to get tenure and had to leave. Weiner explains this by saying that “his colleagues were disappointed by Konopka’s reluctance to publish. Konopka was a perfectionist, and he did not feel he had anything perfect to say about period.” Konopka then took a position at Clarkson College, where he continued to work on period. But again tenure was denied. Konopka is now out of science and: 

lives a few blocks away from the Caltech campus, alone in a small house half hidden by palm trees and magnolias, as anonymous as Kafka’s K. He spends his days collecting butterflies now, tipping his forehead sharply forward to peer at them over his glasses. He also collects Grateful Dead tapes and photographs of local waterfalls. 

In the face of great success, there may also be disappointment. Weiner tells us that 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. 

Delbrück’s depressive feelings recurred. By 1978, shortly before his death, and a quarter of a century after Delbrück had begun his work on Phycomyces, Weiner reports: 

Delbrück still could not understand how a stalk of fungus grows toward light. He confided to his diary that he was sick at heart at the unsolved state of the problem. He had failed to understand the genetics and mechanics of even one simple-seeming piece of behavior. 

Even Benzer, whose enthusiastic temperament permeates this book, can be moved by criticism and self-doubt. Weiner relates that in 1979, after giving a plenary lecture at the Sixteenth International Ethological Conference in Vancouver, Benzer was denounced by Jerry Hirsch, a behavior geneticist, who circulated his criticisms among all the invitees of the conference and to the entire Caltech faculty, saying that he felt Benzer’s work tended to obscure the complexity of behavior and could be used to support racist views. 

Benzer was caught off guard by Hirsch’s attack. It had not surprised him when another student of insect behavior, E.O. Wilson, was the subject of a campaign of criticism when he strayed from his elegant studies of ants and their pheromones to express strong opinions about human behavior. Although Wilson, too, had not expected to be caught in a political struggle, he soon learned that, as the founder of sociobiology, he could not avoid being drawn into the fray. But Benzer was interested in behavioral genetics at a much more molecular level. He was willing to have private conversations about the long-term implications of his work, but he did not take them seriously. His heart and mind were fully occupied with flies, and genes, and molecules. When Hirsch assaulted him, Benzer mounted only a limited defense. 

When somebody denounces you like that, everyone thinks, quite aside from the facts of the matter, “Well, you know.” There’s always this doubt: Maybe the guy has something. 

In the aftermath of Hirsch’s attack (which came on the heels of the death of Benzer’s beloved first wife, Dotty) Benzer made another change in course. He decided to redefine his interest as neurogenetics, instead of the more politically charged behavioral genetics. He would look for mutations that influenced aspects of the development of the nervous system, or that made nerve cells more or less likely to degenerate. Now, at age 77, he is successfully engaged in this line of research, with continuing support from government grants and from private foundations. His most recent paper, about a fruit fly mutant named bubblegum (because of the bubbly appearance of the degenerating brain), was published in the June 18, 1999, issue of Science. The abnormality in bubblegum bears a striking resemblance to that seen in adrenoleukodystrophy, a human disease popularized in the movie Lorenzo’s Oil

A CELEBRATION OF BENZER

What makes Time, Love, Memory so interesting is that it breathes life into the technical details of genetics by relating them to the thoughts, feelings, quirks, and adventures of Seymour Benzer, one of its most gifted, colorful, and inspiring practitioners. We first meet him in 1934, as he takes a microscope—his bar mitzvah present— down into the basement of his family home in Brooklyn to add to his personal laboratory. We are lucky that Benzer had a camera with a timer so that we can see a photograph he took of himself in this laboratory—a handsome youth with a warm smile (which he retains) in front of a lab bench topped by shelves full of bottles of chemicals. 

The book includes other personal photographs. We are, for example, treated to an image of Benzer giving Delbrück a haircut. Weiner tells us that Delbrück traded haircuts with people in his laboratory as a way to save money. (“Max Delbrück and many of the first molecular biologists around him were young and poor, and they created their new science in bohemian high spirits.”) Later we see Benzer trimming the locks of his postdoc, Chip Quinn, who was the first to find memory mutants. 

Weiner has also collected some wonderful stories about Benzer. He tells us, for example, about Benzer’s omnivorous appetite not only for new information but also for food. When Benzer began preparing himself to move from phage to neurobiology these appetites overlapped. Weiner reports: 

Benzer wanted to work from the gene to the neuron to the brain to behavior, and he hoped to dissect them all the way he had dissected the gene. While he thought and read, he asked Dotty to buy brains at the butcher’s shop: sheep, cow, goat, pig, and chicken brains. One by one she brought them home, and one by one he dissected them, usually in the middle of the night. Afterward, he ate them. 

As in his Pulitzer Prize-winning book about evolution, The Beak of the Finch, Weiner takes the approach and the discoveries of a field of science as a text for ruminations about philosophical matters. Behavioral genetics provides many opportunities for discussions about innate human differences and about determinism and free will. In doing this Weiner draws freely on many sources, from Pascal, Schrödinger, and Watson to the Old Testament and the Talmud. 

Weiner also gets Benzer to talk about these matters, although Benzer is much more interested in solvable problems, and prefers to leave these bigger issues to others (“Oh, they can have it. I’ll leave it to them.”) Weiner is happy to take up this challenge, and to remind us that work like Benzer’s does, in fact, aid our thinking about the big picture. 

In the end, the distinguishing feature of this book is how it celebrates science by celebrating a remarkable life. During the time that he was working in his basement laboratory in Brooklyn, Benzer read Arrowsmith, Sinclair Lewis’s novel about an idealistic young medical scientist, a book whose main characters recur as leitmotifs throughout Time, Love, Memory. Weiner repeatedly makes clear how strongly Benzer still identifies with Lewis’s hero, Martin Arrowsmith. He also describes Benzer’s admiration for Max Gotlieb, the German scientist who was Arrowsmith’s hero. It was from Gotlieb that “Arrowsmith learns to scorn the kind of careerist in medicine who thinks only about the practice and the fee: or the kind of plodding scientist who never ventured on original experiments which, leading him into a confused land of wandering, might bring him to glory or disaster.”

If Benzer is Arrowsmith and Delbrück is Gotlieb, Jonathan Weiner is their Sinclair Lewis. All three share an old-fashioned view of science as idealistic and collegial. Just as Arrowsmith’s story inspired so many, so too will Benzer’s. The only difference is that, in the hands of a gifted writer like Weiner, truth is even more inspiring than fiction. 

EXCERPT

From Time, Love, Memory: A Great Biologist and His Quest for the Origin of Behavior by Jonathan Weiner. © 1999 by Jonathan Weiner. Reprinted by permission of Alfred A. Knopf., Inc. 

THE KNOT OF OUR CONDITION

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... 

“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 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.”



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Bill Glovin, editor
Carolyn Asbury, Ph.D., consultant

Scientific Advisory Board
Joseph T. Coyle, M.D., Harvard Medical School
Kay Redfield Jamison, Ph.D., The Johns Hopkins University School of Medicine
Pierre J. Magistretti, M.D., Ph.D., University of Lausanne Medical School and Hospital
Robert Malenka, M.D., Ph.D., Stanford University School of Medicine
Bruce S. McEwen, Ph.D., The Rockefeller University
Donald Price, M.D., The Johns Hopkins University School of Medicine

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