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Welcome to Mind Matterswhere top researchers in neuroscience, psychology, and psychiatry explain and discuss the findings and theories driving their fields. Readers can join them. We hope you will. This week: Genes, Environment, and Depression:How Nurture Can Save You from Your Own Genes _____________________ Introductionby David DobbsEditor, Mind MattersAmong biology's more riveting inquiries is the investigation of gene-environment interactions -- the demonstration that a person's genes constantly react to experience in a way that changes behavior, which in turn shapes environment, which in turn alters gene expression and so on. As David Olds described a few weeks ago, this new subdiscipline is yielding startling insights about how nature and nurture mix to help determine one's health and character. This week reviewer Charles Glatt reviews a study that takes this investigation a level deeper, examining how two different gene variants show their power -- or not -- depending on whether a child is abused, nurtured, or both. As Glatt describes, this study, despite its grim subject, suggests promising things about the power of nurture to magnify nature's gifts or lift its burdens. _____________________ Gene-Environment Interactions:When Nurture Wears a White Hat Charles GlattWeill Cornell Medical College, New York, NY For centuries, philosophers, theologians and biologists have debated the relative roles of inborn traits versus environmentally defined experiences in determining what and who we are. This nature-nurture debate carries fundamental implications for our understanding of self-determination, or free will. Indeed, as research has begun to identify genetic risk factors for certain behavioral traits, these risk factors have already been used in court (see here and here)to argue that punishment should be lessened for convicted felons -- the presumption being that their genes made them inherently more likely to misbehave.The importance and challenge of the nature-nurture debate in behavior has recently spawned a new area of research that looks at the interaction between genetic risk factors and experience in the development of psychopathology. A study led by Joan Kaufman and Joel Gelernter, both of Yale, and published in Biological Psychiatry, has demonstrated what many of us have intuitively concluded, which is that both nature and nurture contribute to who we are. In this particular study, genetic and environmental factors interact to determine risk for depression. In their study, "Brain-Derived Neurotrophic Factor-5-HTTLPR Gene Interactions and Environmental Modifiers of Depression in Children," Kaufman, Gelernter and colleagues found distinct gene-environment interactions in the risk for depressive symptoms. Other studies have found similar interactions, but looked mainly at interactions between single genetic and single environmental risk factors. This study ups the ante by examining various interactions among two genetic and two environmental factors, including a four-way interaction with two genetic and two environmental variables. Where the Money Is Kaufman and colleagues took the approach of bank robber Willie Sutton who, when asked why he robbed banks, is said to have replied, "Because that's where the money is." Kaufman and colleagues focused on the most well known and accepted genetic and environmental risk factors for depression to see how they interacted with one another to alter risk. On the nature side, they focused on polymorphisms -- genetic differences between individuals -- that have been implicated in depression through a variety of methods. The first polymorphism is in the regulatory region of the gene for the serotonin transporter. This polymorphism is the 5-HTTLPR, which stands for the serotonin (5-hydroxytryptamine, 5-HT) transporter linked polymorphism. The 5-HTTLPR has received much research attention because it appears to alter the expression of the serotonin transporter molecule, which is the target of the commonly prescribed serotonin-selective reuptake inhibitor (SSRI) class of antidepressants and is itself implicated in depression. Caspi and Moffit and other research groups have repeatedly found this polymorphism to be associated with depression in the presence of stressful life events. The second polymorphism Kaufman studied is the gene for brain-derived neurotrophic factor, or BDNF. BDNF is a molecule that seems to encourage the growth of new neurons; it appears to be central to brain growth and learning. This polymorphism in the BNDF gene alters the efficiency of secretion of this molecule. Recent studies in animals and humans have shown that BDNF levels are decreased during stress and depression and that SSRIs act at least in part by normalizing the levels of BDNF. (BNDF levels have been shown to rise in response to successful SSRI treatment, as well as in response to successful psychotherapy and, for that matter, exercise. An earlier Mind Matters by Francis Lee and Larry Tecott reviewed a rare paper finding a downside to BNDF. ) Thus it is not hard to imagine that polymorphisms (that is, certain variants) of the BDNF gene might interact with other factors to contribute to depression risk. BNDF and 5-HTTLPR, then, were the "nature" factors Kaufman and colleagues examined. From the "nurture," or environment/experience, side they added two epidemiologically established modifiers of risk for depression -- childhood abuse/maltreatment on one hand and, on the other, positive social support.Please Interact Amongst Yourselves The researchers studied 109 children who had been removed from their parents' care due to reports of abuse or neglect and 87 control children with no reports of abuse or maltreatment. They scored all the children for depressive symptoms such as irritability, crying and reluctance to see friends. High scores on this scale indicate greater depression. They then compared the distribution of these scores in children with different combinations of the 5-HTTLPR and BDNF polymorphisms described above. They found that children with the "bad" form of 5-HTTLPR had higher depressive symptom scores -- but only if they had a history of maltreatment. Bad 5-HTTLPR made it more likely (but not certain) that an abused child would develop depression. But it created no effect on depression scores in children without a history of maltreatment. It was like a seed that had to be watered by abuse. This replicates similar findings in studies by Caspi and Moffit and other groups. Kaufman and colleagues then looked at how the different forms of BDNF might affect this picture. They found that a certain version (or allele) of the BDNF gene amplified the effects of the 5-HTTLPR gene, making it even more likely that a given child would develop depression -- but again, only if the child had suffered abuse. Finally, Kaufman and colleagues looked at the effects of social support. They asked the children about people in their lives whom they could talk to about personal things, count on to buy them things they needed and other, similar signs of supportive relationships, and from the answers derived a social support score. Children were then characterized as having high or low support. The researchers found that high levels of such nurturing counteracted the effects of the genetic risk factors almost completely.Balance of Power As with any behavioral genetic study, one must be careful not to overinterpret these findings, because virtually no study in behavioral genetics is consistently or completely replicated. Nonetheless, some additional points about this paper can help inform us on the nature-nurture debate. First, depression scores and categorical diagnoses of depression were significantly higher in children with a history of maltreatment versus controls even before any genetic analysis was factored in. In a similar vein, the highest average depression score of any genotype category in the unabused control children was lower than the average depression score for any genotype category in the maltreated children; genes alone weren't likely to make the child depressed, but maltreatment alone could. These findings suggest that, at least regarding these specific polymorphisms, nurture beats nature. This conclusion will come as a relief to believers in human free will. It also argues strongly for the identification of children at risk for maltreatment and strong actions to reverse the negative effects of this experience. Charles Glatt is an assistant professor of psychiatry at Weill Cornell Medical College and an assistant attending psychiatrist at New York-Presbyterian Hospital.