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Biomedicine

Don't Worry, Be Happy

Nobel Laureate Eric Kandel explains how genetic research could lead to a new generation of anti-anxiety drugs.

Five Nobel Laureates recently got together to talk about the future of the brain at a symposium to inaugurate MIT’s new Picower Institute for Learning and Memory. One of them was Eric Kandel, a neuroscientist at Columbia University in New York, who won the 2000 Nobel Prize in Physiology or Medicine for seminal experiments on sea snails that illuminated the neurobiology of learning and memory. In a conversation on December 1 with TechnologyReview.com’s biotechnology editor, Emily Singer, Kandel explained how researchers are on the verge of understanding serious psychiatric diseases – and that they may even unlock the biological key to happiness.

Technology Review: Are we on the brink of understanding the major psychiatric diseases? What kinds of developments can we expect to see over the next few decades?

Eric Kandel: We have had an explosion of progress in neurology because of molecular biology, but we have not seen comparable developments in psychiatry. I fully expect in the next 20 to 30 years we’ll see this. We know little about anatomical substrates underlying most mental illnesses. We know that the genes involved are complex, but we haven’t been able to identify them. So we haven’t been able to do what people have done in Huntington’s disease and other neurological diseases, which is take these gene defects and put them into animals and try to delineate the mechanisms of pathogenesis. But that’s beginning to be possible. We’re beginning to identify these genes.

TR: Which of the psychiatric diseases are going to yield their genetic secrets the soonest?

EK: The best examples are the anxiety disorders. We know a lot about the amygdala, a structure that lies deep in brain in all mammals, including humans, and is involved in mediation of emotion. We can make animal models that have panic attacks. We can use those models to understand the neurobiology of fear.

TR: You published a paper in November showing that you could create a fearless mouse by knocking out a single gene that’s involved in encoding fearful memories. Normal mice freeze when they hear a tone that has been associated with an electric shock, but when the mutant mice heard the tone, they wandered happily around their cages. Will mice like this help us discover new treatments for anxiety disorders?

EK: Yes. Once we have genes that enhance or reduce fear, we can manipulate the neural circuitry involved in fear. This experiment might present a new way of treating anxiety. You could develop drugs that modify the action of that gene in the amygdala.

TR: You said during your presentation at the Picower symposium that we need to study anxiety and depression’s polar opposite, happiness, which may open up a whole new realm of psychiatric treatments.

EK: There may be diseases that are not diseases of too much sadness, but of an inability to enjoy life. My aim is to modulate the happiness component independent of the sadness component.

If we had a good neurobiology of happiness, it might provide a new target for antidepressant medications. Right now, antidepressant medication is designed to relieve your misery. But one of the things that strikes depressed people is their “anhedonia,” their inability to enjoy life. Think of the things you might be able to accomplish if you increased your ability to enjoy life. It’s an interesting possibility.

TR: How would this work?

EK: We have done animal research that begins to open up the biology of happiness. When you teach an animal to fear a tone, by pairing it with a painful shock, you see an increase in brain activity in the amygdala. But when you teach it that the tone is safe, by teaching the animal it won’t get shocked when it hears the tone, you see a decrease in activity in that area. You also see an increase in activity in the striatum – that’s the part of the brain where signals for things that bring pleasure are mediated.

TR: This brain area also processes signals for addictive drugs, so how would a drug that targets this area be different than, say, cocaine? How do you tell the difference between drugs that bring happiness and drugs that bring physical pleasure?

EK: That is difficult to distinguish in an animal. Every time you deal with pleasure, addiction is a danger. I would first look for drugs that decrease the fear signal in the amygdala. And I would try to target the drug specifically enough to try to lessen the likelihood it would have addictive properties.

TR: Are there ethical concerns associated with designing drugs that make you happy?

EK: Every area of neuroscience has ethical considerations. Once we have the biology worked out, society will have to decide whether they want to have this manipulated. Maybe we’ll decide we don’t want to develop drugs in this area. They might be addictive, that’s the most likely of the dangers. They also might have antimotivational consequences – they might decrease the willingness to work.

TR: Any candidate drug molecules for happiness yet?

EK: No, we’re not there yet.

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