by Lone Frank
To get into these genetic weeds, scientists resort to molecular studies, which search for the specific genes that increase a risk, whether of schizophrenia or conservatism, and identify how the genes act – what enzymes they produce, how active these enzymes are, and what tasks they perform in the organism. This new category of behavioral genetics, which takes advantage of gene chips and association study models, holds great potential for development. It also holds great potential for headlines. When the media report time and again that someone has found the gene “for” something – the “smoker’s gene,” the “infidelity gene,” the “gene for bad driving” – the underlying study is sure to hail from molecular research.
IN THE EARLY days, this sort of molecular work didn’t garner a positive press. In 1993, when the American behavioral geneticist, Dean Hamer, pointed out that a particular region on the X chromosome appeared to be associated with a predisposition to homosexuality in men, it stirred up a brouhaha. Hamer did not claim he had found a predisposition that would be expressed every time it appeared, or one that is found in all homosexual men, just a predisposition that proved to be statistically over-represented in the relatively small sample of gay men he had studied. His first group of subjects comprised forty pairs of brothers, some of whom were homosexual, and a later study of a new group again found the same region: Xq28.
Various gay organizations went into celebratory mode, because Hamer’s results set the stage for ironclad arguments for equal rights and antidiscrimination measures: since sexual orientation is a part of your biology, others could hardly accuse you of perversion and being unnatural. Outside gay circles, the finding was less popular, particularly among certain religious camps that claimed to excel at converting homosexuals to heterosexuality. In their view, homosexuality was (and is) a behavior choice. Beyond religious groups, there was also resistance. Some shouted that, in the name of political correctness, scientists should not even be allowed to research these sorts of topics. What if a “gay gene” did indeed exist? Would it inspire expectant mothers to ask for prenatal genetic testing, and would some of those to mothers possibly decide to abort a “gay” fetus? Even fellow scientists attacked Hamer for, among other reasons, wanting to reduce complicated psychosocial links to simple biology. “This is the most solid work our group has ever done, but we were forced to abandon it at the time, because it was impossible to get financial support,” Hamer said to me, when I spoke to him much later about the events. “The debate was incredibly shrill and went far beyond the science to pure ideology about gays.”
Increasingly shrill voices were heard later that year when the Dutch scientist Han Brunner found the “aggression gene.” Brunner had studied a Dutch family in which, over five generations, a conspicuous number of men were violent, criminal, and exhibited subnormal intelligence, and had discovered they all carried defective versions of the MAOA gene. This gene codes for the enzyme monoamine oxidase, which breaks down a number of neurotransmitters such as epinephrine (adrenaline), norephinephrine (noradrenaline), and serotonin. In these aggressive men, however, the defective gene blocked production of the enzyme and an overflow of the transmitter substances became available in the brain. The discovery forced the public to consider whether aggression and other impulsive behavior could be traced back to MAOA variations. Some commentators fretted that violent criminals would demand gene tests and use “my genes did it” as a defense; others predicted the screening of problem children and subsequent genetic stigmatization.
Because of these early controversies, the public was happier to get the news that a study had found a genetic key as to why some people have a particular need to throw themselves into experiences and activities that provide a thrill. In two articles published in the prestigious journal Nature Genetics in 1996, American and Israeli researchers independently uncovered a connection between a particular variant of the gene for the dopamine D4 receptor and a thrill-seeking personality. There was even a physiological logic to the link.
DRD4, as the receptor is called, is a protein located on the surface of certain brain cells, especially in the areas of the brain that process emotion – the limbic system. Here, the receptor captures and binds the neurotransmitter dopamine and passes on signals to its cell. How powerful the signal is depends on the structure of the receptor. If you have a particularly long version of the DRD4 gene, you get a receptor that binds more weakly to dopamine and provides a poorer signal. The researchers’ hypothesis was that people who are blessed with the long variant of DRD4 must do something extra special to get their shot of dopamine and its accompanying glow of well-being, compared to the rest of us. While the possessor of a short DRD4 can satisfy his lust for adventure by watching a mountain-climbing flick at the local cinema, the person with a long DRD4 has to put on her boots and trudge up Mount Everest. When the scientists drilled into the data, they found that the long DRD4 variant did not guarantee a personality with a need for thrill-seeking and danger, but it was an important component. That hypothesis was supported when, a year later, a study looking at a group of Japanese subjects reached the same result.
For the first time, behavioral genetics had pinpointed a single gene with a specific effect, and things began to move. In early 1996, a team from the University of Würzburg, led by Klaus-Peter Lesch, announced they had achieved a breakthrough in understanding the personality trait of neuroticism. Roughly speaking, neuroticism involves a tendency toward anxiety, to brooding over problems, and to getting hung up on the negative aspects of life. Lesch’s team found a connection between a subject’s high neuroticism score and a particular variant of the serotonin transporter gene, known as SERT. The gene sits embedded in the surface of brain cells, capturing the neurotransmitter serotonin and sending it back into the cell after it has been released to trigger a signal. One component of the SERT gene is a regulator that determines how much of the protein used to transport serotonin is produced. Akin to DRD4, this regulator is found in shorter and longer variants. In this case, the short version has the effect that less of the transporter protein is manufactured. In Lesch’s study, the subjects with a high neuroticism score typically had one or two copies of the short variant, whereas the less neurotic far more frequently had two copies of the long one.
You can see a recurring pattern. Again and again, the genes that behavioral genetics happens upon turn out to be genes affecting the chemistry of the brain, especially those that control the breakdown of neurotransmitters.
At the same time, these genes are typically promiscuous – they are likely to be significant for many different traits. DRD4 is a good example. According to a study carried out by researchers from the Hebrew University in Jerusalem, not only does it help define our appetite for everything new and exciting, it also plays a role in fine-tuning our sexual behavior. Different variants of DRD4 apparently influence such things as our level of sexual desire, how excited we become during the act, and how well we perform.13 Something similar holds true for MAOA. Since its first appearance with a connection to aggression, variants of MAOA have been implicated in “social sensitivity,” as well as compulsive gambling and psychiatric conditions such as hyperactivity and obsessive-compulsive disorder.
BEYONDTHEIR PRESENCE in the brain and their broad repertoire of effects, there is another common feature of gene variants: their effects are rather small. Molecular studies do not throw off the strapping, healthy numbers of heritability familiar from twin studies: thirty percent, fifty percent, eighty percent. When, for example, scientists look at the extent to which SERT determines neurotic temperament, the short SERT variant can explain eight percent of the overall genetic effect on variability in anxiety. A measly eight percent, you think, but in this business, this is actually very large.
Compare that eight percent to the findings for intelligence, for instance. For over twenty years, Robert Plomin, a professor of child psychiatry at King’s College in London, has searched high and low for IQ genes and found pretty much nothing. Not a thing. In his
latest study, Plomin and his colleagues have studied all six thousand or so British twins born between 1994 and 1996, whom they have followed through the years and measured this way and that. The researchers used gene chips to compare a half million SNP markers in high IQ and average IQ children. The only difference that emerged from these rigorous statistical tests was a marker in a gene for which no one knows the function – a marker that, according to calculations, can provide at most an extra half point of IQ.
“It is, of course, a little disappointing,” the American Plomin says, in acquired British understatement, when I visit his lab in the London district of Brixton. Despite the disappointment, however, he remains in good spirits, and had started to gather support for an international study of ten thousand children across Europe. His expectations were low. As Plomin put it: “We may be able to explain between three and five percent of the variance in intelligence in the next five years, and it may involve hundreds of genes.”
So, what’s gone wrong? It may be, as Dean Hamer pointed out in a commentary in Science magazine several years ago, that researchers need to rethink their whole approach to behavioral genetics. They need, says Hamer, to reject the classic model, which assumes a simple linear relationship between genes and behavior; that a particular gene provides direct access to a particular form of behavior. In other words, genes do not code for behavior, they code for proteins, pure and simple. There is a black box wedged between the two, in which networks of genes work together with environmental factors and with the brain’s physiological development and function to create what we call “behavior.” It is this box researchers must try to prise open.
And they’re working on it. Recent studies have focused on how genes interact with specific environmental characteristics, using the model of disease research. They look for genes that predispose or provide sensitivity to a disease and then look for aspects of lifestyle or surroundings that precipitate this predisposition or sensitivity.
One couple has become known for leading the way in this approach to behavioral genetics: married psychologists Avshalom Caspi and Terrie Moffitt, who are affiliated with King’s College, London and Duke University in North Carolina. Just after the turn of the millennium, their studies took psychiatry by storm.
Caspi and Moffitt gained access to a goldmine, namely, data from almost a thousand New Zealand men whose psychological and social development had been charted for more than twenty years, from the time they were in nursery school. The researchers screened the adults for “antisocial” behavior, defined as problems with aggression and violent criminality, among other things. The next step was to conduct gene tests to investigate whether there was a connection between antisocial behavior and variants of MAOA.
There wasn’t. You could not predict from an individual’s MAOA genes alone whether or not he would have problems. But another factor did come into play: men who had inherited the MAOA variant with low enzyme activity from both their parents had an extremely high probability for developing problems if, at the same time, they were subject to a bad early life experience, with abuse in the home. It wasn’t the gene itself but an explosive cocktail of biological inheritance and childhood experience that contributed to later aggression.
A year later, Caspi and Moffitt conducted a similar study to look at the SERT variants and depression. Once again, the connection between gene variant and psychological condition proved to depend on upbringing. The researchers counted up how many particularly stressful life events the individual had experienced in the previous five years and asked whether he had experienced a clinical depression during that same period. The frequency of depression depended on which variants of SERT the men had. Of those who had two copies of the short variant and had been through more than four major stressful events in the five previous years, almost half had experienced clinical depression. By contrast, for men with the same number of stressful events but two copies of the long SERT variant, only one in four had been clinically depressed.
On top of that, there was a clear effect from childhood abuse. Among the men with two short SERT variants, the risk of being hit by depression as an adult increased powerfully – up to two in three – if he also had been abused as a child. Among those with two long SERT variants, child abuse made no difference in the risk for later depression. The short SERT variant provided an increased sensitivity to depression, and that sensitivity was increased further if the person had a rough childhood.
I’M THINKING ABOUT depression on the train from Washington, DC, to Richmond, Virginia. I’m on my way to meet Kenneth Kendler, who has been a psychiatric epidemiologist and a professor at Virginia Commonwealth University since 1983. I’ve met him before. Many years ago, he graciously granted me an interview at a fancy Copenhagen restaurant, where I enjoyed a big, very rare steak, while Kendler stuck to his vegetarian diet.
The train trip from the nation’s capital is typical Amtrak. It takes a miserably long time; the train moves at a snail’s pace, and the temperature inside is freezing cold, to counteract the sticky humidity of June. A number of passengers are wrapped in jackets and cardigans, a rebuke to the summer that ambles by outside. The view from the window is unvaryingly green, so there is not much to do but read. For entertainment, I can choose from Physiological Medicine, JAMA – the Journal of the American Medical Association, General Archives of Psychiatry, and the American Journal of Psychiatry. I leaf through each in turn, and then my gaze falls randomly on the conclusion at the bottom of the first page of an article in the last journal: “Major depression is a familial disorder, and its familiality mostly or entirely results from genetic influences.”
I scan further up the page. It says that a number of studies of depressive families show that the condition’s heritability is around forty percent. They could have aptly studied my family. Just my first-degree relations would have provided reams of quality data. For instance, there is an unbroken line from my maternal great-grandfather to me, all of whom were hit by depression. Great-grandpa Marinus Hansen – whom I only know from family stories and his glum, grey photo portrait – put a bullet in his forehead; his daughter, my maternal grandmother, was almost subjected to a lobotomy. It was a ghastly but heart-warming story, which I loved to be told as a child.
“Mommy, mommy, tell me about the time your mother almost got lobotomized,” I would beg, and my mother would happily relate the tale. It was, after all, something she’d experienced as a teenager. At that time, my grandmother, who had worked insanely hard for her whole life, broke down into a deep depression. So deep, she had to be hospitalized, and for months just lay in her bed. No one could do anything. Not that they didn’t try. The chief surgeon was particularly generous with electro-shock therapy, but nothing helped. Mrs. Frank was too sick to act for herself, and finally the doctors recommended that the family try one last procedure: psychosurgery.
In the 1950s, medical reports indicated that a lobotomy – where they rummage around with a thin metal spatula in the patient’s frontal lobes, cutting random nerve paths – could relieve very severe depression or, at any rate, bring patients to a state in which they could be sent home. The chief surgeon suggested they give it a go. My maternal grandfather, who knew nothing about psychosurgery or medical treatments in general, was in favor of signing the papers.
It was here I always felt goosepimples, no matter how many times I’d heard the story. Think if they’d actually done it. But the family doctor put his foot down – this would not take place under any circumstances. Instead, he found a psychiatrist, a specialist who lived far away but to whom my grandmother was driven once a week for two years. It helped. I remember the grandmother who emerged only vaguely – she died before I started primary school – but my recollection is of a loving and strong woman. A woman who, after fifty years, no longer allowed herself to be bossed around or to jump through hoops for anybody.
Presumably, my grandmother passed the tendency toward melancholy on to her daughter, my mother, who fell to pieces over
her mother’s illness. She dropped out of secondary school, where everything had been going so smoothly. She spent a couple of years alone with her father. She pretty much stopped eating, eventually developing a metabolic disorder. She never used the word “depression,” but when she talked about her early youth, it had the unmistakable sounds of one long clinical episode. Later, the illness returned with such force that I don’t remember the final years of her life without a shadow coloring everything.
Suddenly, I’m sitting here, half way to Richmond, shivering like a newly shorn lamb in the train’s artificial deep freeze, feeling lucky. Really lucky. In comparison to the generations before me, I have had it incredibly easy. My time as a teenager was not an outright catastrophe, just garden-variety terrible. As to depression, I only have three light episodes to boast about. Moreover, I live in a time not only when depression can be treated quite effectively but when you can also begin to delve into and understand this strange and burdensome heritage, a heritage people once wanted nothing more than to ignore.
IT’S RAINING IN Richmond. A constant drizzle that is not only sad in itself but makes the surroundings grim. Or, rather, grimmer; Virginia Commonwealth University is located in a pretty hideous part of town. The university buildings are bland and new, and surrounded by timeless decay; here and there are old two-storey brick buildings in disrepair, and street-level shops that have gone bankrupt and been boarded up. The neighborhood, the weather, it’s enough to get you down.
Until you turn the corner to West Avenue, when the scene is transformed into an all-American small town, with clapboard houses, overgrown gardens, and tree-lined streets. I glimpse Kenneth Kendler through the large front window of his house. When I get inside, he can hardly conceal his excitement.