“Monday Musings” for Monday August 11, 2014
Volume IV. No. 31/131
Epigenetics, Telomeres, Depression Genes
By Assad Meymandi, MD, PhD, DLFAPA*
Faithful readers of this column recall my article on epigenetics that defies Darwinian theory of evolution. Charles Darwin asserted that it takes millennia to evolve changes in an organism. As I discussed in my previous column,1studies of families in the sparsely populated town of Norbotten in northern Sweden—just six people per square mile—revealed that it takes only a couple of generations to effect evolution. I also discussed the ancient Biblical story in Genesis chapters 41 through 47 that describes the Egyptian Pharaoh’s dream of “seven years of plenty and seven years of famine,” which proves to be relevant to the science of epigenetics and the rapid two-generation-evolution-cycle instead of two millennia.
To recap, epigenetics, a 21st-century science, is the study of changes in gene activities not involving alteration to the genetic code but rather gene activities that get passed down to successive generations. Many scientists, including British colleague, neurologist/polymath, Raymond Tallis, a past National Humanities Center Meymandi Fellow, calls this phenomenon “Darwinitis.” Scientists of the renowned Karolinska Institute, Stockholm, Sweden, have undertaken the painstaking work of evaluating the history of famine and feast in Norbotten to see how it affected the lives of the children. They found that “life conditions could affect your health not only when you were a fetus, but also well into adulthood,” concluding that parents’ experiences early in their own lives change the traits they pass on to their offspring. The result of the study shows that the years the children were well fed, their own subsequent offspring grew up to be healthier and physically bigger.
Epigenetics makes it possible to enhance the activities of the good genes and silence and discourage the activities of the bad genes. The task is not very difficult. To chemically flip the “good” switch, one must introduce a methyl group (CH3) to the side chain of DNA—a very simple procedure; to flip it off, introduce a demethylate compound to suppress the activities of the bad genes.
The exciting science of epigenetics is very much like a switch on the outside of the genetic circuits and genome that influences the behaviors of a gene. The very prefix epi, which means to lie outside of the root structure, helps explains that, while not an integral part of an organism’s genetic code, epigenetics can influence the gene’s activities from the outside. Flipping the switch enhances (i.e., turns on a gene) or inhibits (turns off a gene) deoxyribonucleic acid (DNA) activity.
Now, we are learning that genetic configuration and longevity of a cell is very much related to telomeres, which are the tips of chromosomes. In 2009, Elizabeth Blackburn, Jack Szostak, and Carol Greider won the Nobel Prize in Physiology or Medicine for their elucidation of the structure and maintenance of telomeres. These investigators discovered that telomeres are DNA sequences with a structure that protects chromosomes from erosion and that a specific enzyme, telomerase, is involved in their repair after mitosis.
In daily psychiatric practice, one wonders why the incidence of suicide is so high in so many families irrespective of socioeconomic and religious orientation. Is there a depression gene?
The suicide of Ali Reza Pahlavi, the 44-year-old son of the late Shah of Iran which was followed by the suicide of his sister, Leila Pahlavi, stirred many questions regarding the genetic aspect of depression. We have known depression as a distinct clinical illness since the days of Hippocrates (460 BC–370 BC) and Galen (129 BC–217 BC). It was called melancholia with the fascinating etymology of melon, black; cholia, colon, or black bowel. The ancient clinicians thought the origin of depression was in the intestines. However, Persian physician-polymath, Abu Ali Sina (Avicenna) (980–1037 AD), Abu’l Walid Muhammad ibn Ahmad ibn Muhammad ibn Rushd (Averroes) (1126–1198), and his contemporary colleague, the Jewish physician, Rabbi, theologian, and philosopher, Moses Maimonides of Cordoba (Rambam) (1135–1204) forwarded the theory that depression had to do with the brain and not the guts. In 1150, when he was not yet 25 years old, Rambam described depression and obsessive compulsive disorder(Vasvas) and designed methods of treatment that we today continue to use, namely cognitive behavioral treatment (CBT).
Of course, Avicenna, Averroes, and Rambam used many herbs and botanical products in medicine. Their pharmacopeia was replete with plants, herbs, and roots. Around 350 years ago, Edinburgh University in Scotland created the famous Edinburgh Botanic Garden (yes, they call it Botanic and not Botanical Garden) with nearly 400 acres of plants with the single purpose of copying Avicenna’s pharmacopeia. Avicenna’s medical textbook Cannon of Medicine was taught in all European medical schools well into the 19th century.
Sir William Osler’ s writings have many references to Avicenna, Averroes, and Rambam, the giants of medicine. Three learned colleagues interested in history of medicine, Mohammad M. Sajadi, MD, Davood Mansouri, MD, and Mohamad-Reza M. Sajadi, MD, of Baltimore, Maryland, have written a comprehensive article in Annals of Internal Medicine2 that gives more detail about the genius of Avicenna as a clinician, teacher, author, and polymath. Avicenna’s brilliance continues to shine and give guidance to the teachers of medicine even a millennium after his death.
Fast forward the clock of medical science and technology. We now know that DNA provides powerful clues to understanding disease. Data from the National Institute of Mental Health strongly suggest a particular gene may increase the risk of depression. The scientists have found that people with one form of a protein that transports serotonin, one of the many mood-related neurotransmitters, are especially prone to depression when faced with traumatic events, such as alienation and loss of power, country, and princely positions. The displacement is especially consequential for members of deposed royalties. In exile, these privileged children often forget their native tongue and do not learn the language of their adopted country, which exacerbates the sense of alienation and social isolation.
The version of the particular depression gene prevents the neurons (brain cells) from re-absorbing serotonin, which leads to feelings of sadness and negative mood and may make it harder for them to recover emotionally from a crisis. Depletion of the good juices of the brain (e.g., dopamine), indoleamine (e.g., serotonin), and catecholamine (e.g., epinephrine and norepinephrine) leads to depression. Untreated depression often leads to poor quality of life, addiction to and/or abuse of substances, and other forms of self-destructive behavior, including suicide.
Pauline Theology of Hope, Love, Faith, and Redemption
Just as there are families predisposed to paucity of brain dopamine and familial suicide, I know of many families genetically predisposed to an abundance of brain dopamine, especially in the locus coeruleus and the limbic system, particularly hippocampus, the seat of memory in the brain. This is the biochemical and neuroendocrinological equivalence of Pauline theology of hope, love, faith, and redemption. Fortunate folks with well-endowed dopamine circuitry face adversities and vicissitudes of life with optimism and possibilities. Science has accumulated enough knowledge about the mechanisms of cognition, mentation, and perception and their molecular underpinnings at the synaptic junctions that we can make bold advancements in the area of understanding the nature of the depression gene. In a previously published column, I reviewed the book by the learned science journalist Sharon Begley entitled Train your Mind, Change your Brain, in which she recited her work with Dalai Lama and the interest His Holiness has exhibited in neuroplasticity. One of the strongest findings in neuroplasticity, the science of how the brain changes its structure and function in response to input, is that “it is almost magical to observe the ability to physically alter the brain and enlarge functional circuits…” We may have depression genes. But we also have a plastic brain and chromosomes that have flexible telomere length, making us live even longer.
We now are learning the molecular biochemistry and endocrinology of joy, a constant running brook of dopamine, producing a Straussian symphonic poem of life. Let it be known that joy is not the same as happiness. Happiness is the uncorking a bottle of wine and celebrating an evanescent moment. Joy, on the other hand, is steady, permanent, and life giving. Like a running brook, it is constant and it refreshes. Joy changes the morphology and molecular structure by our brain. And these changes may be brought about by a simple change in our attitude and approach to life. Scientists have shown that by just showing purpose and determination, and by merely uttering positive words and intentions, the level of dopamine in the brain is raised.
Go to: Musings on the History of Psychiatry and the Evolution of Man
*The writer is Adjunct Professor of Psychiatry, University of North Carolina School of Medicine at Chapel Hill, Distinguished Life fellow American Psychiatric Association, and Founding Editor and Editor-in-Chief, Wake County Physician Magazine (1995-2012). He serves as a Visiting Scholar and lecturer on Medicine, the Arts and Humanities at his alma mater the George Washington University School of Medicine and Health.
2. Sajadi MM, Mansouri D, Sajadi MR. Ibn Sina and the Clinical Trial. Ann Intern Med. 2009;150(9):640–643.[PubMed]