Portrait of a Gene Guy

When it comes to questions of human behavior, Dean Hamer, big-gene hunter, is sure he's got the answers.

By Robert Pool|Wednesday, October 01, 1997
RELATED TAGS: GENES & HEALTH, GENETICS
Dean Hamer is a happy man. you can see it in the grin that spreads across his face at the slightest provocation. Now, standing in the hallway outside his laboratory at the National Institutes of Health, Hamer is using that happiness to illustrate a point.

Today I’m only about average happy for me, he says. I found out this morning that the tenant in the house I’m buying hasn’t paid rent for a couple of months, and that started the day on a bad note. On the other hand, he’s looking forward to a date with someone he just met, and the glow of anticipation is balancing out his financial anxiety. But even on a so-so day like today, Hamer says he feels more happy than many people do on a good day. The reason, he suspects, lies in his genes. Psychologists have found that each person gravitates toward a particular degree of happiness, Hamer explains, and this level of cheerfulness and contentment is mostly a matter of heredity. So far, nobody knows which of the 100,000 genes scattered along the human genome Hamer can thank. But some years down the road, when someone pinpoints a gene that puts a spring in your step and a song in your heart, chances are pretty good that someone will be Hamer.

There isn’t a good name for what Hamer does, but it’s tempting to call him a big-gene hunter. Part molecular biologist and part psychologist, Hamer is one of a small but growing group of researchers who look for the genes that shape our individual personalities. Why does Tom plunge into a crowd of strangers at a party while Harry hangs back? Why does Rosie jump out of airplanes for fun but Paula prefers Parcheesi? Why does Charlie see the glass as half empty while Joe sees it as half full?

I believe we’ll find out something important about human behavior by studying its genetic basis, Hamer says. A wealth of studies on families and twins, he adds, show that heredity accounts for between 30 and 70 percent of the variation in personality traits among people.

Of course, that leaves another 30 to 70 percent to be accounted for by the environment, but Hamer thinks that, for now at least, piecing together the genetic side of the puzzle will have a greater payoff. It’s not even clear what the nongenetic factors are, he says. It is clear that they are not the standard things you might expect: your home environment while growing up, the schools you went to, your socioeconomic class. These are all examples of what psychologists call shared environmental factors-- things that siblings have in common--and research, Hamer says, shows they play only a small role in shaping basic personality traits. Instead, he notes, it is the environmental factors siblings don’t share--everything from one’s birth order in a family to a person’s unique life experiences-- that are most influential in forging personality, but no one knows which of these are important and which aren’t. And part of the problem, he says, is that the people who have been looking for these factors don’t take genetics into account. Only by doing so, he thinks, can we divine what role genes play in creating temperaments of every stripe.

He is off to a good start. Last year Hamer and a group of colleagues linked neuroticism--a broadly defined personality trait that includes such things as anxiety, depression, hostility, and impulsiveness-- to a gene involved in the production of serotonin, the same brain chemical affected by the antidepressant Prozac. Shortly before that, Hamer showed that a person’s extroversion and taste for new experiences are tied to a gene that shapes the brain’s response to dopamine, a brain chemical whose effects are mimicked by such drugs as cocaine. And, in his most controversial finding, he linked male homosexuality to a stretch of genes on the X chromosome.

Along the way, he has begun one of the most ambitious projects in science today. With psychological profiles and DNA samples accumulated from hundreds--eventually to be thousands--of subjects, he is working his way through the whole human genome, chromosome by chromosome, looking for any gene that has a noticeable effect on personality. It’s like a giant fishing expedition, he admits cheerfully.

From his résumé, Hamer seems an unlikely student of human behavior. In the 1970s he was the first to put foreign genes into animal cells, and he spent several years studying how those genes are controlled. Then in 1983 he switched to yeast, mapping out in great detail how one particular gene--the gene for the production of a metal-binding protein called metallothionein--is turned on and off. By 1992 he was a section chief at the National Cancer Institute and an acknowledged leader in his field, but, he recalls, he was unsure where to go from there. I was sitting around. I was 40. I was done with the metallothionein project. And I knew I wanted to do something with genetics.

I had a lot of friends with aids. One died within a year, others stayed healthy. It seemed random. Might some genetic variation explain the difference? To explore that question, he began looking for a genetic susceptibility to Kaposi’s sarcoma, the deadly cancer that strikes many homosexual aids patients.

At the same time, Hamer attempted something far more speculative: he began looking for genes linked to homosexuality itself. A number of studies had shown that homosexuality is partly heritable--half of the identical twins of homosexual men are themselves homosexual, for instance-- so such genes might exist. But the evidence also hinted that homosexuality is a complex trait, arising from the interaction of a number of genes and environmental factors. The chances of identifying any one gene were small. I was always thinking, ‘This is never going to work. It’s too complicated.’

As it happened, the Kaposi’s sarcoma part of the study turned up nothing. And now, Hamer notes, it’s obvious why: the cancer is now known to be caused by a virus that strikes people with weakened immune systems. But to his surprise, he turned up the first solid evidence for what others would dub the gay gene.

Hamer had gone fishing in the DNA of 40 pairs of homosexual brothers. His strategy was simple: Brothers share, on average, half of their DNA. So if a particular gene did influence homosexuality, that gene would lie in the half of the DNA they have in common. With data from one pair of brothers, Hamer could narrow his search for a homosexuality gene from 100,000 genes to only 50,000 or so. With data from additional pairs of homosexual brothers, he could collect enough genetic information to close in on areas of overlap among them. In theory, 20 pairs of brothers should be more than enough to help him find the target gene, but in practice it wouldn’t be so clean. It was unlikely, for instance, that every pair of brothers would share any one gay gene, given the earlier genetic studies that found no simple pattern of heritability. So Hamer would look instead for statistical anomalies--bits of DNA that were shared by more pairs of brothers than would be expected by chance.

In a preliminary study, Hamer found that some male homosexuality is passed through the maternal side. So he began his search on the X chromosome, which males get only from their mothers. From each subject he isolated and identified the same set of 22 markers--short, easily distinguished stretches of DNA that vary from person to person and that geneticists use to flag a particular spot on a chromosome. If two brothers shared a marker, chances were pretty good that they shared the genes in the neighborhood of that marker as well. Thirty-three of the 40 pairs of brothers, Hamer found, shared the same set of five markers in a region of the chromosome called Xq28, far too many to be a coincidence. Somewhere in that region, he concluded, was a gene or genes contributing to the homosexuality of these men.

When he published his results in 1993, he landed in an often uncomfortable spotlight. Groups opposed to homosexual rights lambasted the finding, fearing that it might make society more accepting of homosexuality. The scientific community was cautious for another reason. Several times before, researchers thought they had traced a behavior-- usually an aberrant one, such as schizophrenia, manic-depression, or alcoholism--to one chromosome or another, but each time the findings were contradicted by later analyses. The gay gene has stood up well, however. Hamer has replicated his findings, and no studies have yet contradicted them.

Still, the gene itself remains at large, its function unknown. It might, Hamer suggests, be involved in the development of the hypothalamus, a part of the brain that has been shown to differ between homosexual and heterosexual men. Or it might do something totally unexpected, he says. Who knows?

Hamer then began looking for a comparable X-linked marker for sexual orientation in lesbians. Here he had no luck. Female homosexuality does run in families, he says, but there’s no clear indication that it is genetic. Studies of lesbian twins have been inconclusive, and when Hamer rounded up DNA from 36 pairs of lesbian sisters and their family members, he found no evidence of an X-linked genetic marker for female homosexuality. He suspects that women’s sexual preferences may be less genetically programmed than men’s. Some of it is partly social and some is genuinely biological.

Around this time, an nih colleague, Jonathan Benjamin, piqued Hamer’s curiosity with a different question. Years of research, much of it done on fraternal and identical twins, have shown that genetic makeup explains about half the differences in people’s scores on tests on extroversion, conscientiousness, and the like. Why not try to trace personality characteristics to genes or sets of genes?

Here was a project that Hamer could sink his teeth into. He would create a personality-dna database with as many subjects as possible and then go fishing.

For four years now Hamer has been building a high-tech seine to drag through the human genome. It starts with ads for people to enroll in a psychological study. The pay isn’t great, just $40 for a small tube of blood and half a day of psychological testing. But since Hamer needs data from two or more family members, he brings out-of-town siblings, parents, and kids to Washington, D.C., for the exams. The result is a mini family reunion.

Working with family members is worth the cost, Hamer says, because it allows him to avoid the chopstick problem. Suppose, he explains, a researcher was looking for a gene for chopstick use and recruited people for testing at random. The researcher would probably find a number of genes associated with better chopstick dexterity, but most or all of them would simply be genes--such as genes for the epicanthic fold of the eye--that are more common among Asians. How could one tell if any of these genes were really related to chopstick dexterity? As frivolous as the example is, Hamer says, this sort of complication pops up in nearly every genetic study. Sibling comparisons offer a way out: Given a putative chopstick gene, a researcher checks sibling pairs who have different versions of the gene against those with the same version. Only if the genetically unlike siblings are less alike in their chopstick test scores can the researchers announce the discovery of a chopstick gene.

Once his subjects arrive, Hamer takes blood samples and gives them multiple-choice personality tests. They answer hundreds of such questions as, I would rather have a house a) in a sociable suburb, b) alone in the deep woods, or c) in between; or, True or false: When someone hurts me I usually try to get even. Although the questions may seem silly, psychologists have decided from decades of study that they can get reliable profiles of people by analyzing their answers.

One standard test, the neo personality inventory, rates people on five broad scales--neuroticism, extroversion, openness, agreeableness, and conscientiousness--as well as on a number of subscales. Extroversion, for example, is subdivided into warmth, gregariousness, assertiveness, activity, excitement seeking, and positive emotions. Another test offers four temperament dimensions--novelty seeking, harm avoidance, reward dependence, and persistence--that are hypothesized to reflect separate neurochemical systems in the brain. Novelty seeking, for example, encompasses a suite of characteristics believed to be governed by the cells in the brain that respond to dopamine.

Various temperament combinations produce recognizable personality types. Someone high in novelty seeking and low in harm avoidance, for instance, will presumably be drawn to such things as scuba diving and hang gliding, while a novelty seeker who is also a harm avoider might look for safer thrills--trying out new types of food, perhaps, or learning to yodel.

How does Hamer use this psychological data to tease information out of DNA samples? He can go fishing, as he did for the gay gene, looking for correlations between genetic markers and personality or behavioral traits. Or, given a very promising gene, he can test it to see if it correlates with any personality traits. In mid-1995 such a gene came along.

Benjamin, who had come to the nih from Israel, heard from his colleagues there that they had linked novelty seeking to a gene carrying the instructions for dopamine receptors. These receptors stud a neuron’s surface, and when they grab on to a dopamine molecule, they send a chemical wake-up call into the interior of the cell. The gene for the dopamine receptor carries a repeat region that varies from person to person, and this segment of the gene is repeated anywhere from two to eight times, with the most common numbers being four and seven. People have two versions of this gene, one from each parent, and the Israelis reported that those with at least one seven-repeat gene scored significantly higher on tests of novelty seeking than those without. Apparently, the seven-repeat genes produce dopamine receptors that somehow make novelty more rewarding.

With his ready-made database of 315 subjects, Hamer easily checked this claim. He gathered up the DNA samples, then used standard genetic techniques to snip out and measure the length of the gene encoding the dopamine receptor in each sample. When he compared these genetic findings with the subjects’ personality test scores, Hamer found just what the Israeli group had found: people with at least one long version of the dopamine gene were more extroverted, warmer, and more drawn to excitement, but less conscientious and deliberate. The two studies, reported together in early 1996, landed a very big fish: the first replicated report of a link between a gene and a personality trait.

Soon afterward, Hamer was on the trail of another gene. At a meeting at nih, he heard Klaus-Peter Lesch, from the University of Würzburg in Germany, describe finding variations in the regulatory region for the serotonin transporter gene. That intrigued Hamer because the brain chemical serotonin is known to help regulate mood. Moreover, the gene in question was a key player in the serotonin delivery system: it encodes a protein that latches onto serotonin in the spaces between brain cells, making it unavailable for use. Might differences in this gene, Hamer wondered, influence a person’s overall mood?

In examining the gene’s regulatory region--a stretch of DNA in front of the gene that controls how fast the transporter protein is produced--Lesch had found that some people had a longer version than others. The long form of the regulatory region, Lesch and others later discovered, prompts about 50 percent more serotonin transporter production than the short form, implying that people with the long form would have less serotonin available to their brain cells. When Hamer examined his database, he found that people with two copies of the long version were indeed somewhat different from the rest--overall, they were a bit less anxious, more happy-go-lucky.

The link between mood and serotonin transporter regulation, Hamer says, is a preview of where the genetics of personality is headed. Future discoveries will probably involve regulation of a gene, not the gene itself. I’m convinced we’ll find a lot of behavioral variation is due to the level of the protein instead of the structure of the protein. However, most single genes will explain only a small part of a person’s temperament. In the case of the serotonin transporter, the variation in its regulatory region of the gene accounts for a mere 4 percent of the total variation in anxiety traits. That small effect is to be expected, Hamer says, because it’s likely that many genes act in combination to produce a particular personality trait.

Since that finding, he has set his sights on a new target: a smoking gene. A number of genetic factors seem to influence whether someone gets hooked on nicotine, he says. One obvious suspect is the receptor for the brain chemical acetylcholine, which happens to respond strongly to nicotine as well. So Hamer is recruiting smokers and their families for genetic and personality testing.

Meanwhile, Hamer continues to fish. There are 350 markers that cover the entire genome, and we’re doing them one by one. His chances for success depend strongly on the size of his database, which now includes over 1,000 subjects. In his sexual-orientation study, 80 men were enough to land the gay gene, but he was focused on only one very distinctive behavior. Now that Hamer is considering a score of personality traits, he needs a much larger group to guarantee that any correlation he finds isn’t just due to chance. For a gene with a very strong influence on personality, just 100 or 200 subjects might be enough to pick it out, but for genes with weaker effects, several thousand might be needed. It is a tedious, statistically demanding search--Hamer has hired a full-time statistician just to run the statistical analyses--but he believes that eventually he will trace a number of personality traits to particular spots on the 23 pairs of chromosomes. Here’s smoking too much, here’s what makes you happy, and so on. He still won’t have the genes themselves, of course, only their general location on a chromosome, but from there he can hope to isolate the genes.

That sounds frightfully close to a pretty bleak concept: a DNA blueprint for personality. But Hamer doubts that tracing temperament and behavior to their genetic roots will lead people to throw up their hands and say, I can’t help it that I’m sad/anxious/antisocial/murderous. My genes make me that way. Consider happiness, he says: Research on identical twins suggests that 80 percent of long-term happiness--how you feel on average over time--could be genetic. Suppose that someone solidifies that finding by tracking down the 10 or 20 genes that contribute to happiness. Will people then quit trying to be happier? Will they get depressed because someone else has happier genes? Not likely, says Hamer. We each have a happiness range, and we tend to gauge our happiness relative to our own norms, not those of others. Knowing which genes influence happiness--or extroversion or persistence or self-directedness--will give us a new way of thinking about who we are and how we can improve ourselves, and it may make us more understanding of others.

That’s the sunny view of this work. What about the dark side of such knowledge? Will it be abused by employers to screen potential employees or by insurance companies to weed out policy applicants with the wrong genes? Might prospective parents reject certain fetuses? There’s always the possibility of misuse, Hamer says, and we have to guard against that. Indeed, I spend a substantial percentage of my time working on the ethical and social issues. He gives talks, goes to workshops, and has even written a general-audience book on the subject, Living With Our Genes, to be published next year. But he doubts that any of these ethical nightmares will become reality, and he sees many benefits.

I’m convinced that in the end the positives will outweigh the negatives, he says. An understanding of the genes that underlie personality traits should, for example, lead to the discovery of better drugs to treat mental illness and to new ways to help people get over addictions. Perhaps more important, he says, we’ll learn more about ourselves and others. Understanding your genetic makeup is the key to figuring out who you are. This is a tool for liberation, a scientific window into the soul.
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