Insights from Harvard Medical School By Michael C. Miller, M.D.

Newsweek Dec. 8 issue -

Genes don't stop working the day we're born. They're active throughout life, switching on and off in response to cues from the environment. Unfortunately, they don't always respond in optimal ways. For every 100 people born, one ends up with schizophrenia, one develops bipolar disorder and 20 experience some form of depression. Heredity may account for as much as 80 percent of the risk for these illnesses, but we still know little about how, exactly, genes affect our risk. Fortunately, scientists are starting to find clues.

Like the building of the transcontinental railroad, the study of genes and mental health is a race from the ends to the middle. If researchers can pinpoint a suspicious gene in people from afflicted families, they can try to figure out its function. Conversely, if they know something about the physiology of the illness, they can sometimes use that knowledge to zero in on offending genes. Either way, they gain new insight into the biology of the illness.

One of the most important findings to date came out this summer, when a group of researchers from the United States, Britain and New Zealand showed that a gene involved in the brain's use of serotonin affects our vulnerability to depression. The so-called serotonin-transporter gene comes in 'short' (less efficient) and 'long' (more efficient) versions, and each of us inherits two copies--one from each parent. No combination of short or long variants leads directly to depression, but short versions of the gene put people at a distinct disadvantage if they experience stressful life events. In tracking more than 800 young adults over a five-year period, the researchers found that 33 percent of those with at least one 'short' became depressed after a series of stressful life events, such as divorce or the loss of a job. People with two copies of the short variant fared worse than those with a single copy, and their risk of depression rose steadily as their lives became more stressful. By contrast, only 17 percent of those with two 'longs' grew depressed in similar circumstances, and their risk of depression remained flat as their stress levels rose.

No one knows just how this gene exerts its effect on mood, a question that could keep researchers busy for decades. But this study carries seminal lessons. It reminds us that all mental activity is a reflection of brain function, and it illuminates the fascinating interplay between heredity and experience. Genes, as it turns out, don't cause depression. They leave us more or less vulnerable to stressful life experiences. By amassing hundreds of discoveries like this one, we may someday gain a full picture of contentment and despair. The pace of progress may seem glacial. But glaciers change the contours of the world.