What causes disease?
Our illnesses have different origins. Some are purely genetic—caused by mutations in our DNA (alterations in one or more genes)—such as most forms of intellectual disability, including Down syndrome and fragile X syndrome. Others stem from the environment: trauma, accidents, external injury. But the vast majority fall into a third category: multifactorial diseases, which arise from the interaction of genetic predisposition (itself the result of multiple modest DNA variations, each harmless alone) and harmful environmental factors. Most psychiatric illnesses belong here, along with many degenerative diseases like cancer, cardiovascular conditions, common forms of diabetes, and numerous others.
Some environmental hazards harm everyone—think of pollutants or radiation. Others damage only those genetically "predisposed," as gluten does in celiac disease. But many factors considered universally harmful—cigarette smoke, infectious agents—cause different damage depending on each person's genetic capacity to eliminate carcinogens or resist infection. The same holds for environmental factors known to harm mental health: their impact varies with individual biology.
What is epigenetics?
Epigenetics, a term coined in the 1940s, has only recently become the focus of serious research into human disease.
In essence, it studies the cellular mechanisms that regulate how genes function—usually in reversible ways—without changing the DNA itself. These are complex biochemical processes that, while leaving DNA intact, can "activate" or "silence" different genes depending on what each cell needs to do in its tissue at any given moment. This is how all our cells, though genetically identical, become functionally different. The chemical imprint left on DNA by these activating or silencing mechanisms is called the epigenome.
Like a switch: on and off
Consider what happens during normal embryonic development. Each of us begins when a mother's egg fuses with a father's sperm. The resulting cell, the zygote, carries about 24,000 genes from each parent. At every cell division, from the zygote onward through billions of divisions in prenatal and postnatal life, cells copy their DNA and distribute it equally to two daughter cells. In this way, every cell in your body contains the same genes as the original zygote—your entire life long. Yet from the earliest stages of development, cells begin to differentiate: each takes on the specific functions of its destined tissue.
Bone marrow cells that become red blood cells produce hemoglobin because epigenetic mechanisms activate globin genes while silencing keratin and albumin genes. Skin cells specialized for keratin production cannot make hemoglobin or liver albumin. Nerve cells acquire enormously complex functions that other cell types never develop, yet they cannot perform the work of liver or bone marrow or skin cells.
This differentiation happens through selective activation and silencing: the genes needed are switched on; all others are switched off.
Yet the DNA—the genes—remains identical in all these different cell types. A genetic test on cells from the placenta, amniotic fluid, blood, or skin of the same person always yields the same result.
Here is what we now know: the epigenetic regulation that enables our cells to differentiate and function correctly can be disrupted by harmful environmental factors, causing genes to be silenced or activated inappropriately.
For many diseases of unknown cause—those we suspect have only partial genetic origin (the multifactorial diseases)—modern molecular analysis now allows us to study the epigenome in unprecedented detail and compare it between sick and healthy people.
Cancer research provides the clearest evidence. Tumor cells, despite showing significant DNA damage, simultaneously display widespread epigenomic alterations that make them vastly different from healthy cells.
Epigenetics and psychiatric illness
Similar studies have examined other diseases, including childhood psychiatric conditions (particularly autism spectrum disorder and ADHD) and adult psychiatric conditions (particularly schizophrenia and bipolar disorder). In all these conditions, significant epigenomic differences appear between cells of affected people and unaffected people. While these differences cannot yet be confidently called cause or cofactor of the psychiatric disorder, they correlate in statistically significant ways with the known dysfunction of certain neural circuits damaged in these conditions—dysfunction sometimes mediated by neuro-hormonal changes triggered by environmental stress.
Growing evidence confirms that many known environmental factors drive epigenetic disruption. On the psychological side: emotional deprivation, childhood or adolescent abuse. On the ecological side: contamination of various kinds—heavy metals, air pollution. On the nutritional side: toxic exposures or nutritional deficiency, especially maternal malnutrition during pregnancy. These factors cause harm whether they act after birth or, more crucially, before birth or even before conception, when they can act directly on reproductive cells. Increasing evidence shows that some external factors not only create negative epigenetic effects in directly exposed individuals but may affect the next generation through effects on the reproductive cells of the exposed parent.
Research advances on new fronts
While epigenetic studies do not reveal new environmental culprits behind many psychiatric disorders—and therefore do not change primary prevention goals—they illuminate how these factors work and what paths pharmacological research should pursue to improve and personalize treatment. For example: reactivating genes silenced by abnormal epigenetic mechanisms triggered by chronic stress or prolonged maternal malnutrition during pregnancy.
We are still at the beginning of what will likely be a long road toward treating diseases caused by epigenetic disruption. Yet research objectives that were entirely unknown not long ago are becoming increasingly clear.
Mariano S. Pergola
Epigenetics of Psychiatric Disease was the title of the CME course held on May 27, 2017, by the nonprofit association VEDERE OLTRE, in collaboration with the Hospital Medical School and the Regional Center S. Alessio-Margherita di Savoia for the blind in Rome, at the Center's main auditorium. vedereoltre.org
