On Epigenetics and the Epigenome

Monday Musings for Monday June 10, 2013

Volume III, No. 21/124

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Epigenetics and the Bible—Brain and Behaviour Part II

By Assad Meymandi, MD, PhD, DLFAPA*

This is a follow up—Part II–on last week’s “MM” devoted to Brain and Behaviour. Today we discuss the related important topic of epigenetics.

It seems a bit odd to start a discussion of cutting edge, up to the minute, science of epigenetic with an ancient Biblical story: Genesis chapters 41 through 47 talks about the Egyptian Pharaoh’s dream of “seven years of plenty and seven years of famine…”   Well, here is the relevance of the Old Testament to this cutting edge 21st century science:

Actually, there is a place in northern Sweden called Norrbotten sparsely populated, six people per square mile that has offered astonishing epidemiologic and scientific data which have given birth to the science of epigenetics. In 19th century Norrbotten there were literally seven years of famine followed by good harvest and abundance of food.  For instance, 1800, 1812, 1821, 1836, and 1856 (the year of potato famine in Ireland) were years of total crop failure and famine for the people of Norrbotten. But in 1801, 1822, 1828, 1844, and 1863, there was excellent harvest and abundance of food.  Scientists of renowned Karolinska Institute have taken the painstaking work of tracing the effect of this famine and feast to see how it affected the lives of the children.  With these studies, they have established “life conditions could affect your health not only when you were a fetus but well into adulthood”, concluding that “Parents’ experiences early in their own lives change the traits they passed to their offspring.” The result of the study is that the years parents were well fed; their children grew up to be healthier and physically bigger offspring.

In 1967, when the writer was director of Cumberland county Mental Health Center, applying for a grant for the Head Start program, I used a study by Karolinska Institute which was published in the Acta Physiologica Scandinavica, and Lancet, demonstrating that fetus and fetal central nervous system (CNS) exposed to excess secretion of maternal catecholamines and its metabolites, especially metanephrines, vinyl mandellic acid, and 3-methoxy 5-hydroxy methyl glycol (MHPG) produces babies that are more irritable, scrawny, cranky, susceptible to Attention Deficit Hyperactive Disorder (ADHD), and prone to anxiety, phobia and social maladjustment. The project titled “Intrauterine Head Start” was funded and our findings were published. So, the knowledge of environmental influence on fetus is not new. What is new is the epidemiologic studies from Norrbotten in defiance of Darwin’s assertion in his seminal work “On the Origin of Species”, 154 years old coming November 2013 (I will have another ‘MM’ in November marking the anniversary of this seminal work), that evolution takes place over millions of years. The Norrbotten studies suggest that evolution and environmental influence affect genes in one or two generations. It does not take millions of years. This is heretical. Suddenly, we have evidence that Darwin was wrong! It takes only 25 to 75 years, one to three generations, and not millennia for evolution of genes to take place.

 What is epigenetics?

The exciting science of epigenetics as the name implies is “the study of changes in gene activity that does not involve alteration to the genetic code but gets passed down to successive generations…” It is very much like a switch on the outside of the genetic circuits and genome that influences the behaviors of a gene. The very word epi means above explains that this activity while not an integral part of an organism’s genetic code, from outside or above influences the gene’s activities.  In essence it is like a switch that may turn on or off the activity of a gene.

In Utero Cell Differentiation

A cell in the kidney and the cell in the brain, a neuron, have the exact same DNA. The nascent cell can differentiate only when crucial epigenetic processes turn on or turn off the right gene in utero. This is why studies of identical twins show why one sibling develops asthma or bipolar disorder, even schizophrenia while the other is perfectly normal. The studies from Norrbotten clearly show that because of epigenetic switch you can pass down epigenetic changes in a single generation.

There are several epigenetic drugs on the market. 5-Aza-cytidine (produced by Celgene Corporation is an example of an epigenetic drug that prolongs the life of patients afflicted by severe myelodysplastic syndromes, MDs). By turning a switch that is outside of the genome sitting on DNA, one enhances (turns the gene on) or inhibits (turns the gene off) of DNA’s activities. Cutting edge science is after discovering how to enhance the activities of the good genes and how to silence and discourage the activities of the bad genes. The task is not very difficult.  To chemically turn on the good switch is to introduce a methyl group (CH3) to the side chain of DNA, a very simple procedure. Or vice- versa, remove demethylate (take the methyl, CH3 group off) the compound and suppress the activities of the bad genes. In recent years FDA has approved three other epigenetic drugs that are thought to stimulate tumor suppressing genes. It is hoped that we will find drugs that turn off expression of genes of many diseases including cancer, Alzheimer’s, autism, and schizophrenia, even alcoholism.

In the case of Alzheimer’s disease, where blobs of starch like gunk or amyloids are deposited in the brain interfering with transmission of messages in nerve cells (neurons) causing dementia, by using the instrument and knowledge of epigenomics, it is conceivable to find the switch (the epigenome) that turns off the dumping of amyloid in the neural synaptic clefts. Currently, the National Institute of Health is investing heavily in better understanding and codifying epigenomics. The Human Genome project completed in March 2000 found that the human genome contains approximately 25,000 genes. Private enterprise, and Craig Venter, who won the Nobel Prize in Medicine or Physiology in 2005 bested government bureaucracy and completed the project ahead of the government by two years. We had Venter’s book reviewed in this space a few years ago. Now we need a massive project to identify the epigenome and compile the human epigenomic book. The number of epigenomes far exceeds 25,000 and the cost of completing the project will cost hundreds of billions of dollars. Besides, it will cause a bad case of Darwinitis. We will keep you posted as the science of epigenomics further develops.

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*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.

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