PSYCHOLOGISTS, psychiatrists and neuroscientists have jousted for years over how much of our behavior is driven by our genes versus the environments in which we grow up and live. Arguments have persisted because there has been little hard evidence to answer basic questions: How exactly do genes and environment interact to determine whether someone will become depressed, say, or schizophrenic? And can environmental interventions such as drugs or psychotherapy really alleviate disorders that are largely determined by genes?
A field called epigenetics has finally begun to address some of these issues. Its practitioners study how tiny molecules stick to, or become unstuck from, two main targets in a cell's nucleus: the DNA in and around a gene and the histones—the proteins around which chromosomes spool. These tiny molecules are known as methyl and acetyl groups, and their presence or absence at target sites controls whether particular genes can generate proteins, the workhorses of most physiological processes.
Until a couple of years ago, the conventional wisdom in biology held that such molecular changes occur in primitive cells, usually during embryonic and fetal development, not in mature cells such as a child's or adult's neurons. Then researchers proved that epigenetic changes are indeed at work in mature cells. Now studies are starting to show how environmental cues can stimulate epigenetic changes that could contribute to several psychiatric diseases. Systematic measurement of those changes could eventually indicate how the environment influences the genetic chemistry underlying many human behaviors.
Schizophrenia and Depression
One condition that has begun to yield its epigenetic secrets is schizophrenia, which generally arises when people hit their late teens or twenties. “Something happens during puberty that causes changes in gene expression,” notes Dennis R. Grayson, an associate professor of psychiatry at the University of Illinois at Chicago.
That “something” is still unknown. Schizophrenia has not been definitively tied to mutant genes, even though it tends to run in families, and environmental factors show only weak statistical links to the disease's incidence. But it is becoming clearer that epigenetic alterations—triggered perhaps by a convergence of subtle influences—may play a role. Grayson and his colleagues Alessandro Guidotti and Erminio Costa autopsied the brains of schizophrenic patients and found that methyl groups were attached to a gene that helps to form connections between neurons. Earlier postmortem studies showed both a sharp reduction in this gene's activity and an increase in the activity of a gene that promotes attachments of methyl groups to DNA.
Experimental evidence links epigenetic changes to depression as well. Eric J. Nestler, psychiatry department chair at the University of Texas Southwestern Medical Center at Dallas, has proposed a potential animal model of the disease that includes epigenetic changes in the hippocampus, a memory-storing brain region that actually shrinks in some cases of human depression.
To develop this model, Nestler and his co-workers put a small adult male mouse into the cage of a far larger aggressive mouse, which soon attacked the newcomer. Ten minutes later they placed a plastic barrier between the mice, which stopped the attacks but did not stop the little rodent from seeing, hearing and smelling its nemesis. A small mouse placed in this situation for 10 days typically displayed depressionlike social avoidance.
The researchers discovered that such treatment also caused methyl groups to stick to histones (the DNA-spooling proteins) in the hippocampus. This action suppressed a gene that, as a result, failed to generate a protein suspected of helping the brain adapt to stress. What is more, the small mouse ceased exhibiting social avoidance when it received antidepressants, which restored the gene's activity.
Nestler says he does not know yet how a hostile environment prompts methyl groups to stick to histones, but his study suggested why the antidepressant works: it causes acetyl groups to attach to the histones, thereby counteracting the effects of the methyl groups. Nestler and other scientists are now trying to create compounds that will tinker with specific epigenetic mechanisms.
Fearfulness is another psychological condition that can arise from the epigenetic effects of environmental influences. Michael J. Meaney, a psychiatry professor at McGill University, has found that when a rat pup receives less licking and grooming from its mother it is more fearful and more reactive to stressors as it matures.
The team found that a hippocampal gene sheds methyl-group molecules during the first week of a pup's life if its mother is a “high licker.” Pups of low lickers do not prune the molecules. An adoption experiment proved that licking triggers these events: when the team entrusted pups born to mothers of one licking type to mothers of the other type, the genes' methyl status reflected the licking type of the adoptive parent. Licking is believed to exert its effect by raising the pups' thyroid-hormone production and activity of the neurotransmitter serotonin.
Meaney says he encountered “a fairly intense level of skepticism” when he first presented his results, because they imply that epigenetic changes can occur in mature cells, not just in the immature cells present in an embryo or fetus. The social implications of his work were also unsettling. The findings suggest that a mother's parenting style can have very different effects on the activity of a child's genes. Meaney and others are now also studying hundreds of human mother-infant pairs to learn how a stressful pregnancy might affect a baby's later development.
Applying epigenetics to the brain is just beginning, but the field is ramping up as technologies to monitor molecular changes improve. Do not expect the findings to bring speedy cures for psychiatric ills, however. For years, cancer researchers have investigated epigenetic influences on tumor formation, yet cancer remains unvanquished. Epigenetics may indeed unveil what is happening at the intersection of genes and environment—between nature and nurture—but we will be relying on psychiatrists and psychologists for a long time to come.