The Fly in the DNA

In San Francisco I once knew a woman who had been adopted as a baby. When first I met her she hadn’t seen her mother since the day she was born, and had never met her father or any other blood relative. When she was twenty-one years old, she managed, somehow, to track down her mother, who was then living in central California with a man, not her father, and four other children. My friend wrote to the family and was invited to visit them in their large, noisy house on the outskirts of a large town. On the day she arrived she stayed up talking late into the night. Finally everyone went to bed. But at around three in the morning my friend woke up. She often got hungry in the middle of the night, and was in the habit of making plain spaghetti at two or three in the morning. She decided to go down to the kitchen to see what was there. To her astonishment, she found her mother standing by the stove, boiling a pot of spaghetti. “That’s how I knew she was my mother,” my friend said. “She ate spaghetti in the middle of the night, just like me.”

Who are we, really? How much of what we do is a learned response to the assaults and rewards of life and how much is programmed in our genes from the moment of conception? This question is hardly new, nor are answers expected any time soon. One would expect recent advances in molecular biology to settle this issue once and for all, but they seem only to be adding to the confusion. In Time, Love, Memory, the science writer Jonathan Weiner takes us up and down the evolutionary ladder, looking for clues about the behavior of human beings from the DNA of insects and mice, and from the scientists who study them.

During the last forty-five years, a great number of discoveries about how cells work and how plants and animals develop have issued from molecular biology labs all over the world. In the 1950s and 1960s, many of the pioneers of the new biology were former physicists who realized that the kind of bold experimental and theoretical approaches that led to discoveries about the structure of the atom and quantum mechanics might also be applied to the study of life. In Time, Love, Memory, Weiner deals with the work of Seymour Benzer, who was in his twenties when he decided to leave physics and become a biologist. During World War II he worked in a top-secret government lab on semiconductors, and others would later build on his work to develop the transistor. Weiner suggests that, for the young Benzer, physics—or at least the physics in which he specialized—just seemed too easy. Benzer’s friends were eager to carry on their work in solid-state physics, or to set up lucrative electronics companies, but Benzer worried that the entire field was becoming pedestrian. On the other hand, in the late 1940s, biology posed truly mysterious questions about how living things are made.

Benzer took biology courses, apprenticed himself to several important biologists in the US and France, and soon made a name for himself in the painstaking field of gene mapping. Then, in the early 1960s, that old feeling came back. Gene mapping, it seemed, was becoming old hat too. By this time Benzer had had two children and had watched them, practically from the day they were born, behave like distinct individuals, as though some internal program were unfolding in their brains. At the time, the feeling was growing among molecular biologists that in their laboratories, all of life’s mysteries would eventually yield up their secrets. Mind, behavior, and personality were the deepest mysteries of all. What, Benzer and some of his colleagues wondered, might genes tell us about them?

Studies of geese, bees, cats, and other organisms seemed to suggest that animal behavior often follows inherited patterns. Without being taught, bees know how to pollinate flowers and cats know how to chase small, speedy objects. After spending a year doing little else but read about psychology, talk to his biologist friends, and think, Benzer decided to study the genes governing the behavior of the fruit fly Drosophila melanogaster.

The fruit fly is a winged insect about the size of Thomas Jefferson’s ponytail on the American nickel. It has big red eyes, a brown or black body, and six tiny wires for legs. It lives on moldy fruit and is thought to have evolved in Africa, where it cruises heaps of fruit and garbage around markets. Biologists have been studying fruit flies since the early part of this century, and these insects adapt well to laboratory conditions. They are born, reproduce, and die all in the space of a month or so, are not fussy about what they eat, and have a set of giant chromosomes that are easily visible under a cheap light microscope. By the time Benzer decided to become a fruit fly expert, scientists had already learned a great deal about genes and the development of embryos from studying them.

Fruit fly behavior is simple, and for Benzer this was a distinct advantage. If you wish to become an architect, you do not start by building Versailles. You would probably be better off starting with something small, like a shed. In the same way, if you want to study behavior, it is wise to start with something that doesn’t do very much.

Benzer began by making careful observations of fruit fly habits. First, he found that, like people, flies sleep at night. They also nap during the day, an instinct that may once have served to help them escape from the midday African sun, which can quickly dehydrate a tiny fly. Benzer hired an intelligent, meticulous postdoctoral worker named Ron Konopka, whose task was to find mutations in genes that affected a fruit fly’s sense of time. Eventually he found a strain of flies that overslept, didn’t take naps, and didn’t go to sleep on time with the other flies. Other researchers eventually showed that these flies had a mutation in a gene they called “period,” which encoded a molecule shaped, amazingly, like a little spring. It is not known whether this molecule works like a watch spring, but genes that resemble “period” are found throughout the animal kingdom, even in people, and it is possible that these genes have something to do with sleeping cycles in all animals.

Another of Benzer’s postdocs, named Jeff Hall, decided to study the sexual life of fruit flies. When fruit flies mate, an adult male approaches a virgin female and does a little dance with its wings, either in front of her or be-hind her, and then mounts her from behind. The pair spends a few minutes in sexual congress before detaching from each other. Within a few days, the female starts laying hundreds of eggs.

It was the dance that Benzer and Hall were interested in. Many insects dance, perhaps most famously the bee, which wiggles in front of its hive to tell its colleagues where the nectar is. Biologists had long suspected that the dances of insects were somehow hardwired in their brains. Hall studied a strain of flies in which the males shunned female flies and danced with other males instead. What’s more, these mutant males often formed long chains, with one fly hooked up to the posterior of another, and danced soul-train fashion all around the glass bottles they lived in. This behavior, like the deranged sleeping patterns of “period” flies, was also caused by a single mutation, this time in a gene they named “fruitless.”

A third postdoc in Benzer’s lab, named Chip Quinn, studied the intelligence of flies. Flies can learn simple things, especially about danger. If you put a fly on a piece of metal connected to a battery and throw the switch, it will fly away. Quinn put flies in tubes with metal platforms, blew in different odors, and gave the flies electric shocks. Eventually, after several such lessons, the flies got to know that certain odors meant trouble and avoided them. This ability seemed to be governed by a small number of genes. If one of these genes were damaged, the resulting fly could never learn about odors and electric shocks, even after many lessons. Another scientist later constructed an improved fly by engineering it to express an extra copy of the gene that encodes a molecule called “cyclic AMP- responsive element-binding protein,” which interacts with some of the fruit fly intelligence genes. This fly learned to avoid odors after only one lesson, and never seemed to forget it.

Weiner says this is equivalent to a forty-year-old man remembering a telephone number he had been told only once as a twelve-year-old child. In fact, this seems more like a forty-year-old remembering he got one hell of an electric shock when he was twelve; but even if Weiner overstates the achievement of the fly, the identification of this gene is no less an achievement for the scientists involved.

The story of the search for behavior genes in the fly is an impressive one and Weiner tells it well. He has a tendency, however, to be a bit grandiose. Throughout Time, Love, Memory, Weiner quotes portentously from Pascal, Dante, Proust, William Blake, various Greek philosophers, and other wise men, and seems to suggest that the eternal questions they posed are being somehow addressed by Benzer’s fruit fly experiments. The rhetoric is not altogether convincing. For example, in answer to Blake’s “Tell me what is a thought, & of what substance is it made?” Weiner writes sarcastically, “as if [Blake] were asking an unanswerable question.” Somehow, I don’t think Blake would have found “cyclic AMP-responsive element-binding protein” a satisfactory explanation of his inner life. Nor would Bishop Berkeley and Saint Augustine consider the problem of the meaning of time to be solved if someone had told them that a molecule called “period” regulates daily sleeping and waking cycles in an insect, or even in all animals. Without “period” we would still feel loss and despair, and still grow old and await death. We might have insomnia more often, but we would experience the tragic effects of time all the same.

Benzer’s experiments are brilliant in their own right, and Weiner’s attempt to connect them to the musings of philosophers can seem forced. But there is something even more worrying about Weiner’s book. For Weiner and for many of his biologist protagonists, the studies of fruit flies and their genes have implications for human behavior as well. Like Benzer’s extraordinary fruit flies, some people sometimes have insomnia, some men desire other men, and some people aren’t very bright. This has led many journalists and scientists to suppose that human beings, like fruit flies, are genetically programmed to behave in certain ways. The National Institutes of Health now provides about $30 million every year for research into genes alleged to affect personality. The search is now on for genes governing intelligence, depression, alcoholism, adventurousness, homosexuality, anxiety, and many other traits. How successful are these efforts likely to be? And what are the implications for humanity?

According to Weiner, in the long view molecular genetics bids to “unite all of the sciences, all of philosophy, and all the arts.” I am not sure what he means by this. Will musicians someday learn more about symphonies if they dig up Beethoven and examine his DNA? Will philosophers learn anything new about dialectics from Hegel’s DNA? Weiner does not elaborate, but quotes the Harvard biologist Edward O. Wilson, who tells him that he believes that complex human behavior is only explicable through an understanding of human genes. Perhaps the most dispiriting vision of what behavioral genetics has in store for humanity comes from Lee Silver, a professor who studies mice at Princeton University. Weiner learns from Silver that scientists will soon be using computers to analyze our personalities. He writes, “By screening the DNA of one hundred thousand people, combining that information with personality tests, and letting a computer crunch it all together, molecular geneticists will put together gene complexes working together to produce the most complex traits of personality.” Soon, says Silver,

we’ll be able to take ten thousand people and match different combinations of [genes] across the whole genome and come up with a behavioral profile…. My feeling is that molecular biologists are going to move into psychology and take over the field.

In this way, Silver aims to find, for example, the genetic basis of shyness. “Knowing nothing about the gene, the environment, the psychology or the physiological machinery, you can find your way in. With the kind of mass screen Silver is envisioning,” Weiner writes, “he could find two dozen genes, each with multiple alleles, that contribute to shyness….”

Weiner is so excited about the prospect of having all our DNA put through this gene analyzer that he seems to get his facts a little confused. “Soon it will be straightforward,” he tells us, “to take a small sample of someone’s DNA [and] at a glance a molecular geneticist will know what genes that individual carries and what genes are on right now and what genes are off.” Not so fast. One can tell what genes a person carries by inspecting the DNA in any tissue, such as a sample of blood or a small piece of skin. However, in order to see what genes are having an effect (or, as molecular biologists usually say, “expressed”) in any given tissue, a scientist must remove that tissue from the body, pulverize it (electric blenders are commonly used), and carry out tests on the resulting goop. Since most genes affecting behavior are likely to be expressed in various regions of the brain, I do not think that our molecular geneticist of the future will have many volunteers.

Here and there, Weiner admits that the outside world of human experience is also relevant to how people behave, but his main argument seems to be that someday scientists will find the genes that overwhelmingly determine human personalities. The scientific community does not speak with one voice on this issue, to say the least. Weiner interviewed some scientists who question the wisdom of looking for behavioral or personality genes, but he casually dismisses them without examining these arguments in any detail. Most, he argues, are Marxists, who see human genetics as some sort of class conspiracy. He portrays Richard Lewontin, the respected geneticist and critic of both the human genome project and human behavioral genetics, as a grouchy Luddite who forces his students to sit through lectures about radical philosophy. Lewontin has presented highly informed and telling analyses of the powers and limitations of human genetics,¹ but one wouldn’t know this from Weiner’s portrait.

The only other skeptic Weiner introduces is Max Delbrück, one of the ex-physicists who founded molecular biology and then won the Nobel Prize. Delbrück spent his last years in a basement lab at the California Institute of Technology trying, without much success, to figure out how fungus spores grow toward light and away from darkness. Near the end of his life, when he was already aware that he was dying of cancer, Delbrück was invited to give a commencement speech at Caltech. “Indeed,” he said,

we can take it for granted that science is intrinsically incapable of coping with the recurrent questions of death, love, moral decision, greed, anger, aggression…. Science does chatter and chirp incessantly, sweet music to those few who are tuned in to it, but does it satisfy Aurora’s yearnings [for eternal life], Aurora the morning dawn?

This poignant speech, unusually humble for a molecular biologist (at least in my experience), does not impress Weiner. For him these are only the ramblings of a dying man whose convictions about science changed because his experiments on fungus didn’t work.

But Delbrück may have had a point. The search for genes that determine human behavior and emotions has been underway for two decades or even more, and it is worth having a look at what is known so far. Scientists know that some mutations in human genes have enormous effects on behavior. For example, if a child is born with an extra copy of a gene on chromosome 21, he or she will have Down’s syndrome, a severe form of mental retardation that is often associated with heart problems. There are many other inherited forms of mental retardation, known to be caused by mutations in other genes. But the new geneticists are looking for subtler variations than this. They want to know about everyday behavioral characteristics. For example, why do some people have higher IQs than others? And why do some people become alcoholic, shy, homosexual, or depressive while others abstain from alcohol, are outgoing, heterosexual, or always look on the bright side?

For a number of years, headlines announcing the discovery of genes governing alcoholism, manic depression, schizophrenia, reading disabilities, compulsive gambling, violent behavior, and a long list of other human traits have been followed—sometimes very quickly—by other statements modifying or retracting the claims made about such genes. There is still no confirmed identification of a gene that controls human behavior or personality, apart from extreme cases like Down’s syndrome. This does not mean that our behavior and capacities are not governed by genes. Our brains are products of evolution and our every molecule comes from genes. The difficulties in mapping genes thus far may well have been technical ones. But it is also possible that molecular geneticists have been going about this project in the wrong way.

Weiner is a behavioral genetics enthusiast, and he describes studies of three human genes that scientists think may explain certain types of behavior. These genes are said to govern homosexuality, “novelty-seeking,” and happiness. Do the studies of these three genes signify the dawn of the bright future of human behavioral genetics? Weiner thinks so, but his arguments are less than convincing. For one thing, if a strain of flies has a mutation in one of its intelligence genes, or in the “period” or “fruitless” genes, every fly will behave in the same stereotyped way, according to which mutation it carries. The same goes for the mutation that causes Down’s syndrome in human beings. If a child inherits this mutation, he or she will have a particular range of mental defects. On the other hand, none of the three putative human personality genes seems to have such consistent effects.

Dean Hamer, a molecular geneticist at the National Institutes of Health, noticed that homosexuality sometimes runs in families. Men who are gay sometimes have gay brothers and gay uncles as well. He decided to study the DNA of a group of gay men recruited from HIV clinics and gay men’s organizations in Washington and their brothers. If both brothers were gay, Hamer found that it was more likely that both brothers had inherited a stretch of DNA on the X chromosome called Xq28 than would be expected by chance. In other words, it looked as though Xq28 was particularly common in these gay brothers, and this suggested that it might be a genetic marker for homosexuality in general.

Since Hamer only identified the region of the X chromosome where the putative gay gene might be, and not the actual gene itself, he was not able to say how the gene worked or how common the gene was in the general population, or whether, say, Oscar Wilde had it. From Weiner’s book, one might come away with the impression that since there is a gene that makes male fruit flies dance in long, soul train-style lines and circles, it is reasonable to assume that there is a gene governing human homosexuality as well. But it is not clear how the weird behavior of these mutant fruit flies relates to human homosexuality, which takes many forms and is expressed differently in different cultures and at different ages. In any case, the claims for Xq28 are already in doubt. A recently published study from Canada failed to find any connection between Xq28 and homosexuality.² Perhaps Hamer’s gene doesn’t determine gay behavior after all, or perhaps it only does so in people from Washington but not in Canadians.

Meanwhile, a group of Israeli scientists have been wondering why some people are skydivers and war reporters and others are stay-at-home housewives and librarians. In 1996 these researchers found that a mutation in a gene encoding one of the receptors for the brain chemical dopamine seemed particularly common in people classified as “novelty seekers,” according to their answers on a questionnaire. The “novelty-seeking” mutation was also found more often in a group of Chinese heroin addicts than in a group of Chinese people who were not heroin addicts. However, a series of recent studies have shown that the mutation is not particularly common in novelty seekers from Finland or Baltimore. A study of novelty-seeking among Americans of African and European descent, with and without substance abuse or other psychiatric problems, also failed to find any association between the trait and the dopamine receptor gene. Moreover, even the optimistic estimates of the discoverers of the “novelty-seeking” gene suggest that it accounts for about 4 percent of total variation in the trait. In other words, at least 96 percent of the trait arises either from other genes or from the experiences that individuals are exposed to in life, or, perhaps most plausibly, from how a particular person felt on the day he filled out the questionnaire.

Similarly, Hamer and his colleagues also recently identified a “happiness” gene, which encodes a molecule that carries the neurotransmitter serotonin back into nerve cells after it has been released. Mutations in this gene have been linked to unhappiness and anxiety in some, but not all, studies. Again, even the happy gene’s advocates admit that it probably accounts for no more than 3 to 4 percent of all variation in anxiety-related personality states.³

If genes for personality and behavior really are important for human beings, one might expect that genes governing particular traits would be particularly common in certain populations. Maybe there is a politeness gene that is more common among Japanese people, or a gene for amorousness that is more common among Italians. Certainly important disease genes seem to work this way. For example, sickle-cell anemia is found mainly in West African blacks,⁴ a group that has been exposed for generations to malaria, and Tay-Sachs disease is most common among Ashkenazi Jews, a group that is relatively inbred and therefore harbors a number of harmful genetic mutations.

How is the “happiness” gene distributed among human beings? According to one recent study by J. Gelernter and his colleagues at Yale University, it is scattered throughout the world, in almost all populations, to a greater or lesser degree. It could have drifted through world populations at random, like any silent mutation that has no important effect at all.⁵

Weiner apologizes for the lack of clear results from human behavioral genetics, assuring us that the “work was [presented] too soon.” Perhaps. But it should be clear that personality does not work itself out in life in a straightforward way. Some gay men flirt with women too, and some librarians are skydivers. In the Israeli study, “novelty seekers” were identified by questionnaire as being “impulsive, exploratory, fickle, excitable, quick-tempered and extravagant” as opposed to “reflective, rigid, loyal, stoic, slow-tempered and frugal.” I wonder if anyone really fits neatly into one or the other of these categories. Some people who are frugal are also quick-tempered. Some people are extravagant at Christmas and frugal the rest of the year, or the other way around. Some people are frugal and quick-tempered and stoic and reflective one day, but reflective and fickle the next.

Shirley Hill of the University of Pittsburgh, who has been trying to identify genes governing alcoholism, recently argued that much of the difficulty she and her colleagues had encountered arose from uncertainty in the diagnosis of alcoholism.⁶ Some people drink throughout the day, some binge on weekends, others drink only under stress or at boarding school or after a divorce. Determining who is really alcoholic is not a straightforward process. But if Dr. Hill cannot define alcoholism, in which you can at least measure how much people drink, how easy will it be to define far more abstract qualities such as “happy,” “novelty-seeking,” or even “homosexual”?

The Harvard psychologist Jerome Kagan argues that psychologists know too little about what the basic elements of personality and behavior are. For example, “anxiety” has a biological basis, in that it is associated with increased blood pressure and heart rate, sweating, and other physiological signs. However, one can detect changes in these signs in people who are experiencing a variety of mental states other than anxiety. There is a scene in Thomas Mann’s The Magic Mountain in which Dr. Behrens and Hans Castorp discuss the biological mechanism behind goose bumps. “‘The sebaceous glands have little muscles that can make the glands stand up erect,’ Behrens explains, ‘and when they do that, your skin feels like a rasp—just like the lad in the tale when the princess dumped a pail of minnows over him.”‘ Hans says he remembers the tingling feeling he had at his confirmation. “‘Yes,’ Behrens said, ‘a stimulus is a stimulus. The body doesn’t give a damn about the meaning of the stimulus. Whether minnows or communion, the sebaceous glands stand up erect.”‘ How particular mental states correlate with events in the brain and the rest of the body is still largely unknown.

Doctors have always endeavored to give our problems names, but this does not mean that all these names mean anything. In view of its doubtful claims, human behavioral genetics today seems a bit like phrenology, the eighteenth-century science that held that the key to personality was contained in different bumps on the brain that could be felt through the skull. Just as there are now some who believe that there are genes for happiness and “novelty-seeking,” phrenologists thought there were bumps on the head corresponding to poetic talent, comparative wisdom, banality, and love of one’s mother. Jerome Kagan points out that the particular behavioral problems psychologists are preoccupied with today are the afflictions the twentieth century has deemed most important.⁷ The same can be said for geneticists. If a group of human behavioral geneticists were to enter a time machine and go back to the eighteenth century, they would not look for genes governing IQ, novelty-seeking, anxiety, or alcoholism. They would very likely look for genes for desire, godliness, and chastity.

It is hard to understand how some molecular geneticists can ignore the powerful effects of the outside world on how people feel and behave. Hunger can make people more “reactive” to stressful stimuli, as can states of intense concentration. Molecular geneticists often use questionnaires to evaluate who is “anxious” or “novelty-seeking” and who is not. If one answers a questionnaire when one is hungry or has been concentrating on something else, how reliable is the diagnosis of “anxious” likely to be? Anxiety tends to be particularly common among people with financial problems and with small children. According to Kagan, the social class of a child’s family is the best predictor of his or her vocation and personal traits as an adult.

A person’s “novelty-seeking” behavior and anxiety levels may also be partly influenced by his or her experiences in the womb. Studies of pregnant monkeys who are subjected to stress by being put in a box in an empty room and being blared at through a loudspeaker have found that persistent changes take place in the brains of their babies. As juveniles, these offspring have higher levels of stress hormones, are more fearful, and are less likely to explore novel objects in their cages.⁸ Similar changes are believed to take place in the brains of the children of stressed human mothers.

If a person’s mental state can be affected by his social class, what he had for breakfast, whether he is preoccupied with something, or whether his mother was under stress when she was pregnant, how is a geneticist such as Lee Silver going to determine who is really “shy” and who is not? What does being “shy” mean anyway?

Our personalities presumably have their physical sources in the cortex, the folded sheet of cells on the surface of the brain. Human beings have a bigger and more elaborate cortex than any other animal. If you were to take the cortex of a chimpanzee, with whom we share all but 1 percent of our DNA, and iron it out flat, it would be about the size of a sheet of typing paper; an ironed-out human cortex would be four times as big. The Oxford neurobiologist Susan Greenfield has argued that the cortex is what makes our behavior different from that of animals in at least one very fundamental way:

Humans have the least stereotyped, most flexible lifestyle of all animal species, and it is believed the cortex must therefore in some way be related to liberating the individual from fixed, predetermined patterns of behavior. The more extensive the cortex, the more an individual will be able to react in a specific, unpredictable fashion in accordance with the dictates of a complex situation. The more extensive the cortex, the more an animal will be able to think for itself.⁹

Unlike most other parts of the human brain, and nearly all parts of the brains of animals, certain regions of the cortex are not clearly associated with any particular function; they seem instead to integrate many functions, such as seeing, hearing, touching, awareness, spatial skills, and dexterity. Our emotional states may emerge from a process in which the cortex places us in space and time, and gives us a sense of our current situation. There is no evidence that the brains of such animals as fruit flies can do this.

We are designed to be sensitive to our social environments. Like the gazelle who bolts when she hears a leaf rustle in an unfamiliar way, we perk up in social situations. We adapt to them, not by natural selection on our genes, but by altering our behavior. We are constantly aware of that little voice heard on the first day of school, warning “adapt, or else.”

Some general human capacities, such as an ability to learn language or even to develop a sense of right and wrong, are almost certainly inherited. However, one will speak differently and have a different moral sense depending on whether one lives in Buckingham Palace, Washington Heights, or Papua New Guinea. What other human characteristics might be inherited? Before blundering around in the lab with a test tube of DNA, scientists might be wise to at least try to discover more about human development and behavior first. If there are important genes at work, at least scientists will know what to look for.

In my university introductory physics textbook there was a picture of a man sitting in an antique cushioned chair. He was tall and slim, with a neatly trimmed beard and mustache, and he wore a well-tailored black suit. He sat with his legs crossed, in an insouciant slouch, one elbow propped on an armrest. A cigarette in a very long holder dangled from long, aristocratic fingers. This was Prince Louis-Victor de Broglie, discoverer of the theory that light can behave as both a particle and a wave. De Broglie expressed his theory in a single mathematical equation, and his Ph.D. thesis, for which he won a Nobel Prize, was one page long. To me de Broglie was physics personified, its elegance, directness, and simplicity.

The discoveries of molecular biology so far have owed much to the elegant, pared-down approach of the physicists who turned to the study of living things in the 1950s and 1960s. Genes have provided science with a model for embryonic development and they should provide industry and medicine with new techniques for fighting disease. But without considerable contributions from other disciplines, we can doubt that molecular biology will have much that is meaningful to say about the human mind. To understand how people respond to the world will make enormous demands on the imaginations of scientists, and will require a deeper understanding of who we are, from the outside in, as well as the inside out.