Tuesday, November 9, 2010

Genes as mirrors of experience in the study of mental illness

From The NY Times:

For decades, researchers have ransacked the genetic pedigrees of people with mental illness, looking for common variations that combine to cause devastating conditions like schizophrenia and bipolar disorder. The search has stalled badly; while these disorders may involve genetic disruptions, no underlying patterns have surfaced — no single gene or genes that account for more than a tiny fraction of cases.

So scientists are turning their focus to an emerging field: epigenetics, the study of how people’s experience and environment affect the function of their genes.

Genes are far more than protein machines, pumping out their product like a popcorn maker. Many carry what are, in effect, chemical attachments: compounds acting on the DNA molecule that regulate when, where or how much protein is made, without altering the recipe itself. Studies suggest that such add-on, or epigenetic, markers develop as an animal adapts to its environment, whether in the womb or out in the world — and the markers can profoundly affect behavior.

In studies of rats, researchers have shown that affectionate mothering alters the expression of genes, allowing them to dampen their physiological response to stress. These biological buffers are then passed on to the next generation: rodents and nonhuman primates biologically primed to handle stress tend to be more nurturing to their own offspring, and the system is thought to work similarly in humans.

Epigenetic markers may likewise hinder normal development: the offspring of parents who experience famine are at heightened risk for developing schizophrenia, some research suggests — perhaps because of the chemical signatures on the genes that parents pass on. Another recent study found evidence that, in some people with autism, epigenetic markers had silenced the gene which makes the receptor for the hormone oxytocin. Oxytocin oils the brain’s social circuits, and is critical in cementing relationships; a brain short on receptors for it would most likely struggle in social situations.

At least one group of researchers argues that chemical markers help resolve a biological competition between maternal and paternal genes in the developing fetus. In the traditional view of reproduction, genes from the mother and father work together as collaborators, sharing the duties of creating a new life. But a novel theory holds that the genes are in fact in competition, at various points along the newly forming fetus’s genome. If the system goes awry and brain development tilts too strongly toward the father, a result can be autism, these scientists suggest; too heavily toward the mother, and the child may develop mood disorders.

“A lot of the model systems we have studied suggest that epigenetic modifications impact behavior, and also that those effects can be reversed,” said Thomas Lehner, chief of the genomics research branch of the National Institute of Mental Health.

By studying genes at the “epi” level, scientists are hoping to discover patterns that have been elusive at the level of the genes — and ideally to find targets for calibrated treatments that would not simply shut off errant genes but would gradually turn their activity up or down, like adjusting the balance on a stereo.

The National Institutes of Health is sponsoring about 100 studies looking at the relationship between epigenetic markers and behavior problems, including drug abuse, post-traumatic stress, bipolar disorder and schizophrenia, compared with just a handful of such studies a decade ago.

In one large study of people with schizophrenia, researchers at Johns Hopkins are analyzing blood and other data to see whether the degree of epigenetic variation is related to the inherited risk of developing the disorder. In another, researchers at Tufts are studying the genes of animals dependent on opiates to see how epigenetic alterations caused by drug exposure affect the opiate sensitivity of the animals’ offspring.

Other researchers are trying to determine whether areas of the genome that show large epigenetic changes can help uncover underlying genes that contribute to mental disorders.

Dr. Lehner notes that such studies are expensive, and that the findings may be as difficult to decipher as studies of the genes themselves. But experts agree that any effort to understand how genes affect behavior must take into account how experience affects genes.