1 Boring Old Man

It is an obvious fact that a single celled embryo ultimately generates the many different cell types in an adult, yet each of these cells contain the exact same DNA. The study of whatever is responsible for this diversity is known as epigenetics. If all cells have all genes, how is it that some cells selectively express only a few, while other cells express a completely different set? What a fascinating question! Worthy of much research. It is, indeed, one of the hot topics in biology today, as it should be:

Early life influences risk for psychiatric disorders

"Early Life Programming and Neurodevelopmental Disorders" by Tracy L. Bale, Tallie Z. Baram, Alan S. Brown, Jill M. Goldstein, Thomas R. Insel, Margaret M. McCarthy, Charles B. Nemeroff, Teresa M. Reyes, Richard B. Simerly, Ezra S. Susser, and Eric J. Nestler. Biological Psychiatry, Volume 68, Issue 4 [August 15, 2010]…

^{For more than a century, clinical investigators have focused on early life as a source of adult psychopathology. Although the hypothesized mechanisms have evolved, a central notion remains: early life is a period of unique sensitivity during which experience confers enduring effects. Neurodevelopmental disorders, which include mood disorders, schizophrenia, autism and eating disorders, have been associated with fetal antecedents such as maternal stress or infection and malnutrition. Sex is another factor that influences the risk for psychiatric disorders through poorly understood mechanisms.}

^{We know little as to how the maternal environment alters offspring programming. Epigenetics, an area of research that is studying how environmental factors produce lasting changes in gene expression without altering DNA sequence, may provide new insights into this question. A new review, published in Biological Psychiatry, has "incorporated the latest insight gained from clinical and epidemiological studies with potential epigenetic mechanisms from basic research," explained first author Dr. Tracy Bale. These key findings are from a conference on Early Life Programming and Neurodevelopmental Disorders held at the University of Pennsylvania.}

^{For example, the authors discuss findings where maternal stress has been associated with an increased risk of schizophrenia in male offspring and may alter fetal brain growth. Data also indicate that maternal stress, infection, and/or exposure to famine contribute to an elevated risk for depression in offspring. Of critical importance, the brain continues to develop into adolescence, and so later influences, such as exposure to child abuse and/or neglect, must also be taken into account. Studies have consistently shown that adults who experience maltreatment as children are at a much greater risk of developing mood disorders.}

^{Clearly, multiple factors are at play that influence an individual’s disease risk. By applying the principals of personalized medication, one can view this science as "personalized prevention," as it aims to apply these principals earlier in the pathological process. Understanding and defining these disease mechanisms at the very earliest points in life could help identify novel targets in therapy and prevention.}

But there’s something else to say about this abstract. It’s based on the observation fact that people who have a bad time of things in early life are prone to misery as adults. There’s not much news there. Authors have written about that for centuries. Psychoanalysts, learning theorists, psychotherapists of all ilks have talked about how a dismal childhood leads to an unquiet mind [the operative word here is mind, not brain]. People [like me] have spent whole careers talking to unhappy people trying to help them sort out how their previous experience in life has discolored their adult perceptions and emotions. Were we deluded? Were we talking to people about the wrong things when we should really have been looking at their epigenetic something or another, selecting some appropriate chemical intervention based on their genome? I personally kind of doubt it, but my bias is obvious.

Back to the abstract. There are a number of assumptions that deserve our skepticism. In the world of Charles Nemeroff, sadness and unhappiness are elements of a mood disorder. And in his world, a mood disorder has a biological basis. In a few cases, that’s probably true. It’s called Manic Depressive Illness [bipolar disorder]. But in modern times that possibility has been magnified astronomically. While we don’t have a solid biological marker to discriminate those patients, we do have some reliable clinical criteria for identifying them. Very few of the people I see meet those criteria, yet in a modern world, one hears "I have a chemical imbalance" or "I’m bipolar" from patients all the time, even here in the back woods of Georgia. To say it’s an oversold idea doesn’t do justice to the ubiquity of this idea.

In the world of Charles Nemeroff, negative experience in childhood causes adult unhappiness via some as yet undefined genetic/epigenetic mechanism rather than by influencing the developing mind. In fact, he never mentions the mind. Never mind, always brain seems to be his mantra. Further, in the world of Charles Nemeroff, "personalized medicine" means picking the right treatment [drug] based on the patient’s personal endowment [genetics]. I’ll leave you to evaluate the studies he bases this assertion on but I’m beyond unimpressed. It’s an idea that he and his colleagues find exciting. I’d be excited too if there were some evidence for it.

But there’s yet another point to make. If we made the unlikely assumption that everything in this abstract were to turn out to be ultimately true in some hypothetical future time – unhappiness = depression = mood disorder = biological = mediated through some epigenetic/genetic mechanism = treatable by some "personalized" drug – Charles Nemeroff is not going to be the person who discovers that pathway. Nemeroff is a break-through freak. He’s spent his career trying to find some spectacular piece of biology that will immortalize him for all times [and pay for his lavish lifestyle]. He’s chased corticotrophin releasing factor, vagus nerve stimulation, lithium patches, abortion drugs  in depression [Mifepristone eg RU-486], almost any psychoactive drug [particular ones whose makers pay him], etc. etc. looking for a break-through to put him on the map. He’s not a careful scientist who follows a line of inquiry and knows a dead end when he sees it. He has made a career of looking for the silver bullet, ever ready to jump on any speculation that might lead him to find the pot of gold at the end of the rainbow. And worse, his ethics are universally questionable. He’s apparently able to spin anything into an exciting break-through, a Glenn Beck with a white coat, an Oz behind a curtain. He stepped down as an editor when he published a review touting his own fantasied break-throughs based on – well actually who knows what it was based on. He was fired as Chairman at Emory after repeated ethical violations [that he lied about for years]. He has danced between ethically challenged and just plain crook throughout his career. This is not the kind of person that makes scientific discoveries. If there’s a scientist who has made a genuine contribution to our body of scientific knowledge with a story like Nemeroff’s, I’ve never heard of him/her.