Thanks for the Anxiety, Grandma: Epigenetics and Mental Illness

"The Favorite" by Georgios Iakovidis courtesy of Wikimedia Commons
“The Favorite” by Georgios Iakovidis courtesy of Wikimedia Commons

By Sara Knight
BU News Service

You eat right, you exercise, you meditate daily. You had an ideal childhood with loving parents and a healthy social life. Cigarettes and alcohol? Never! And yet despite your textbook health precautions and lack of turmoil, you find yourself diagnosed with a serious mood disorder. Why? The answer may lie with the type of childhood one of your grandparents experienced – maybe your maternal grandfather was neglected as a boy and experienced social isolation from his peers. This obviously extreme illustration may be overly simplistic, but current research hints that this story may not be all that ridiculous or fictional. In mice, researchers have found evidence of grandparents’ distress manifest in the genetic code of their grandpups.

Developing a psychiatric illness may not rely so much on the genes you inherit, but rather the accessories that accompany them. Evidence is mounting that chemical changes on genes actually contribute to certain mental illnesses, not the presence or absence of a gene itself. These alterations, called epigenetic markers, influence how lively or inertly a gene acts and result directly from environmental factors. Intriguingly the evidence that these changes are heritable is also mounting, meaning for example your grandfather’s lifestyle could affect your likelihood of suffering schizophrenia. Because the changes are simple chemical reactions they may be also reversible – a fact that excites many doctors frustrated by the trial-and-error style of most psychiatric medications.

The backbone of this research is a fusion of developmental biology and genetics called epigenetics, epi- meaning “above” in Latin. Developmental biologist Conrad Hal Waddington coined the term in the early twentieth century to describe, for example, how a blood cell is able to “know” how to function as an oxygen carrier rather than a liver cell, despite containing the same instruction manual (DNA) as the cells within the liver. ‘Epigenetics’ refers to molecular “light switches” that act on DNA, telling which genes to turn on and which to turn off.

These switches consist of different molecular markers attached to your DNA. Methylation, or the addition of a methyl group to a segment of DNA, effectively tells a gene to stop interacting or to increase its output within a cell. The changes can also tighten or loosen the coil around your DNA – the looser the coil the more likely the DNA will interact with other chemicals, causing increased expression.

Epigenetics. Image courtesy Flickr user AJ Cann

Environmental stressors, diet, and exposure to chemicals all affect the changes to your DNA that can lead to altered expression. This means that your environment leaves a physical imprint on your genes and subsequently affects how your DNA is expressed. Epigenetics silences the old nature versus nurture “debate” – our genetic material (nature) is honed by our environment (nurture); there is no actual discrepancy between the two.

Doctors have used epigenetics to examine differences between cancerous cells and their healthy counterparts, but now some epigenetics researchers are setting out to tackle the notoriously complex problems presented by mental illness. Diseases like schizophrenia, depression, and bipolar disorder possess a genetic component – they run in families but there has been no conclusive “smoking gene” to predict who will develop the conditions. Mental illness and childhood trauma correlate; leading researchers to hypothesize early stress may trigger alterations on genes important in mental illness.

Researchers found mice that were traumatized in early life had grandpups with DNA that was more heavily methylated – indicating the trauma’s physical alterations on their genes could be passed down their familial line. In 2010 Isabelle Mansuy, a neurobiologist at the University of Zurich, randomly separated mice pups from their moms for a period of 14 days immediately after their birth. After that stressful period, she raised the pups normally. Mansuy found the pups that suffered early trauma had epigenetic modifications on genes related to emotional regulation and stress response. The genes were more heavily methylated. This reflected in the behavior of the mice – they had a higher incidence of the mousey version of depression and anxiety, namely increased stress and lowered grooming and social behavior.

Most intriguingly Mansuy’s male mice seemingly passed on their early ordeal’s genetic legacy through their sperm – their pups also showed the same methylated DNA despite a lack of early trauma. Dr. Tracy L. Bale of the University of Pennsylvania has found that the genetic effects of early stress can be seen in up to three generations of mice, even if the subsequent two generations are raised without stress or separation. Bale also has isolated key developmental windows in which mice are particularly vulnerable to modification.

Were the mice born with genes “marked” for depression and anxiety, or were they simply born more sensitive to environmental stressors? The research community has not reached a consensus, but Bale found the telltale methylation in the mouse sperm, indicating it is a physical transmission. Not all researchers are convinced though, especially when humans are involved.

These molecular light switches are fused onto our DNA through simple chemical reactions, leading many researchers hopeful about potential treatment options. Medications could potentially reverse these modifications and change how a gene functions, as happens in several cancer medications currently on the market. Understanding the underlying causes of mental illness could lead to an increased ability for doctors to intervene before symptoms hit. “The implications are huge from a social public health standpoint,” says neuroscientist David Dietz of the University of Buffalo. He believes that being able to identify and treat vulnerable populations means the next generation “may not be in such a doomed state.”

Though most of the hard evidence for generational transmission has been found in mice, researchers have collected retrospective data on humans that hints the same may be true for us. Researchers Alan S. Brown and Ezra Susser, both of Columbia University, linked prenatal malnourishment to an increased incidence of schizophrenia in children conceived during the Dutch famine of 1944. Humans, however, have lengthier lifespans and less motivation to faithfully participate in multi-generational studies compared to mice, so researchers have a much harder time gathering convincing data. Most human epigenetic studies concerning mental illness are ongoing and the evidence is anecdotal.

Neuroscientists studying epigenetics are still in the first phase of discovery – techniques need refining before any grand statements can be made. Researchers like Johns Hopkins researcher Zachary Kaminsky is working towards developing cleaner research techniques by cataloguing different kinds of genetic markers that may indicate the sort of genetic changes found in mental illness.