Ahmad Hariri stands in a dim room at the Duke University Medical Center, watching his experiment unfold. There are five computer monitors spread out before him. On one screen, a giant eye jerks its gaze from one corner to another. On a second, three female faces project terror, only to vanish as three more female faces, this time devoid of emotion, pop up instead. A giant window above the monitors looks into a darkened room illuminated only by the curve of light from the interior of a powerful functional magnetic resonance imaging (fMRI) scanner. A Duke undergraduate--we’ll call him Ross--is lying in the tube of the scanner. He’s looking into his own monitor, where he can observe pictures as the apparatus tracks his eye movements and the blood oxygen levels in his brain.
Ross has just come to the end of an hour-long brain scanning session. One of Hariri’s graduate students, Yuliya Nikolova, speaks into a microphone. "Okay, we’re done," she says. Ross emerges from the machine, pulls his sweater over his head, and signs off on his paperwork.
As he’s about to leave, he notices the image on the far-left computer screen: It looks like someone has sliced his head open and imprinted a grid of green lines on his brain. The researchers will follow those lines to figure out which parts of Ross’s brain became most active as he looked at the intense pictures of the women. He looks at the brain image, then looks at Hariri with a smile. "So, am I sane?"
Hariri laughs noncommitally. "Well, that I can’t tell you."
True enough: On its own, Ross’s brain can’t tell Hariri much. But a thousand brains? That’s another matter. Hariri is in the midst of assembling a large cohort of Duke undergraduates and gathering key information--brain scans, psychological tests, and genetic markers--for the Duke Neurogenetics Study. From this mountain of data, Hariri believes he’ll be able to learn a lot about Ross, about himself, about all of us. As a result, someday he may be able to read your DNA and determine your innate level of anxiety, your propensity for drinking, and a range of other psychological traits.
It was just a decade ago that Hariri and colleagues at the National Institutes of Health published what is widely considered the first study linking a particular gene to how our brains work. His subject at the time, the serotonin transporter gene, encodes a protein that helps move the regulatory chemical serotonin into neurons. People carry either short versions of the gene, long versions, or one of each. During the 1990s scientists found that having at least one short version of the serotonin transporter gene increased the odds of suffering from extreme anxiety. The results were intriguing, but other studies failed to confirm a connection.
Hariri and his lab director, Daniel Weinberger, wondered if they could get more concrete answers by comparing people’s genes not just to their behavior or a subjective psychological state, but to brain activity measured by a scan. So they embarked on a study of 28 people, half of whom had one or two short copies of the serotonin transporter gene, and half of whom had two long copies.
The subjects entered the fMRI scanner, where they were shown three faces at a time and asked to indicate which two faces matched. That was a ruse: Hariri wasn’t interested in how well they matched faces. Instead, he wanted to measure how the emotional expressions on the faces triggered changes in each subject’s brain.
In line with prior research, the NIH team had found that fearful or angry faces triggered a strong response from the amygdala, a region of the brain that helps us recognize threats. Now the group found a new nuance. People with a short copy of the gene had a stronger response in the target region of the brain than those with two long copies. Hariri’s success inspired other scientists to look for that connection in other people. All told, almost 30 studies have confirmed the finding and linked short serotonin transporter genes to depression and anxiety-related disorders, marking one of the most replicated associations in psychiatric genetics to date.
To Hariri, it makes sense that it is easier to connect our genes with brain activity than with emotional experiences. The way we feel at any given moment is the result of a staggeringly complex combination of factors. The amygdala interacts with many other parts of the brain, and experiences shape the responses of each of those regions. Genes may influence our emotions, but only by tweaking the way our neurons function. "I’m saying, let’s move closer to what genes actually do," Hariri says.
Hariri is quick to point out that the serotonin transporter gene is only one small part of the story of our emotions. He estimates that it may account for at best 10 percent of the variation in how people’s amygdalas respond to scared or angry faces. Other genes may also shape how we respond, and our unique personal histories may play a role as well. When it comes to genes and personality, "we’re at the earliest stages of understanding," he admits.
Over the past decade Hariri has looked for evidence of how other genes affect other aspects of our minds, including self-control and memory. The job hasn’t been easy. One of his challenges has been deciding which genes to investigate.
A traditional way to target a candidate gene is to identify a molecule or process important to, say, emotion, and then go back and find the genes that control it. Serotonin is already known to be involved in emotion--antidepressant drugs like Prozac bind to serotonin transporters--so it makes sense to look to the serotonin transporter gene to help explain variations in people’s emotions. Scientists can also find clues by studying severe genetic disorders. Certain mutations might cause severe retardation, for instance, pointing to specific places to look for a link between genes and intelligence.
But this kind of search is very slow and of limited scope. In 2009 Hariri found a way to accelerate his search. He realized that the new commercial genetic testing labs springing up had the technology he needed to find many more behavior-related genes. For a fee, the California company 23andMe can examine a million different sites in a customer’s genome. Variations at those sites have been linked to diseases such as diabetes and Alzheimer’s. Hariri recognized that he could redirect 23andMe’s test results to his own ends, trawling the data for gene variants linked to the brain activity he recorded in his scans. The more people Hariri studied, the more confidence he could have that these links were authentic. His hope is that a thousand subjects might be a large enough sample to detect even genes that have only a weak effect on the brain.
In January 2010, the Duke Neurogenetics Study was launched. The volunteers, a group that took no psychiatric medicine, underwent a battery of cognitive tests and a psychological interview, in which a researcher asked about their personal history, including drug and alcohol use and the stressful experiences of their lives. Then each subject spent an hour in an fMRI scanner while Hariri ran tests. In one, subjects were shown the terrified or angry faces. In another, they were shown the back of a playing card and asked to guess whether the number on the other side was high or low. Correct guesses could win up to $10. Previous studies have shown that even a simple game like this can activate the brain’s reward-processing regions, for which Hariri wants to find the genetic controls. After the scans, volunteers donated saliva samples for genetic testing at 23andMe.
Each time Hariri and his collaborators added another 200 volunteers to their database, they updated their findings to see if any patterns had emerged. Already they have found some promising results in a gene that codes for a brain enzyme called FAAH. Variations on the FAAH gene can alter how people perceive threats and rewards. Hariri has found that students with a high reward response report drinking more than other students when they experience stress--but only if they also had a lower-than-average threat response. "That’s the double whammy," he says. But the results are preliminary. It is possible that by the time Hariri gets all 1,000 subjects into his database, that particular link will have vanished. "We have our fingers crossed it will still be there," he says.
Hariri’s long-term goal is to create a comprehensive genetic test for the mind. "It’s a dream of mine," he says. Such a test might show how well Prozac or some other psychiatric drug would work on one particular person’s depression. It might also tell people how vulnerable they are to anxiety in the aftermath of a traumatic event.
Knowing their vulnerabilities might allow people to protect themselves in advance. In previous studies, Hariri found that a certain amygdala response makes subjects more prone to anxiety, but only if they lack a strong social support network. If researchers could identify and screen for the responsible genes, such people would know that solitude could leave them vulnerable. "It’s not like we have to spend a decade in a lab to develop a drug," Hariri says. "Friends and family might work."
Copyright 2012 Carl Zimmer