never mind…

Posted on Monday 30 August 2010

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:

The abstract below from the journal Biological Psychiatry takes the idea of epigenetics to a new height:
"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.
While I’ve written for the full paper as only the abstract is available online and haven’t yet received it, there are several points that one can consider just from the abstract itself. First, there are two names in the author list that ought to be familiar to us all by now: Thomas R. Insel [Director of the National Institute of Mental Health] and Charles B. Nemeroff [Chairman of Psychiatry at the University of Miami and notorious Conflict of Interest offender]. Recall from my flurry of posts recently [and the posts of many others], it has been alleged that Dr. Insel used his position at the NIMH to help Dr. Nemeroff get the job at Miami as payback for favors rendered in the past [who is not telling the truth? yes…]. All parties involved deny this allegation, though Insel did finally admit that his actions "may have created the appearance of favoritism" [the Nemeroff Defense]. If the two of them aren’t in cahoots, how come their names are both on this paper you might ask? While it’s a legitimate question, this kind of guilt by association argument won’t stand up in court. What about this one? At a recent CME presentation, Dr. Nemeroff had a session entitled, "Neurobiological Predictors of Treatment Response in Major Depression: Moving Towards Personalized Medicine in Psychiatry." And at this year’s APA Meeting, Dr. Nemeroff presented, "Genes Will Someday Help Select Depression Treatment" – mentioned in the Psychiatric News." Again, no guilt here. It’s just a topic of his interest. But if you look at some of the studies he used in his reporting, they’re pretty damn shaky [how’s your life…]. The article above and Nemeroff’s recent presentations suggest to me that he’s on a new kick. He’s aiming to say that in the future, we’ll send depressed patients to a genetics lab and pick their drug/treatment based on their genotype. And it appears that the Director of the National Institute of Mental Health is on board with Nemeroff’s futuristic notion. It all sounds like a prequel to grant applications to me.

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.

So what does that say about the other authors of Early Life Programming and Neurodevelopmental Disorders? Guilt by association? The only thing I can say about that is that if you’ve ever met careful scientists and snake oil salesmen, you’d know which category he falls in within five minutes of listening to him talk. These other authors have spent a lot more time with him than that. So either they are a uniquely unintuitive lot, or – well, just or…
    August 30, 2010 | 11:28 AM

    Now I will reveal my bias too — it’s clearly for an understanding of how early experience sets the pattern for later mood, self-esteem, character traits, behavior, interaction, achievement, etc. etc. etc. The answers are to be found in concepts of quality of attachments, patterns of interaction, self-concept, the lasting effects of trauma, etc. etc. etc.

    This is the stuff we learned from Freud, Melanie Klein, John Bowlby, Sullivan, Kohut, Dan Stern, etc etc etc

    People like Nemeroff will never let their research lead them toward these kinds of explanation because there is no money involved. No research grants, no pay-offs from discovering and hawking products. Just the satisfactions of understanding human beings and being helpful to them in a lasting way.

    They are not physicians, nor even scientists. They are essentially market researchers and entrepreneurs. What’s most lucrative for them personally determines what they follow and what gets “discovered.”

    It’s a sorry perversion of their supposed professions are physicians and scientists.

    August 30, 2010 | 1:35 PM

    Thanks for this post. I found Nemeroff meeting w the Dalai Lama almost laughable, in fact I did laugh years ago when that conference was held. Those 2 together, talk about polar opposites. The Insel/Nemeroff scandal is proof these ppl are just “too-big-to punish” and are above any prosecution in the US for silent crimes, such as pocketing boat loads of money at the expense of innocent victims (consumers and patients) such as Nemeroff did. The fact he moved to the U of Miami to reside in his mansion that GSK built —and got hired via the Insel “kind words” is gross. Makes me glad I’m not an academic having to deal w these ppl as colleagues every day. Frankly, it is the stories of ppl such as Nemeroff that gave me my critical thinking about psychiatry, that based on watching my own child suffer at the hands of the 4000% increase of pediatric bipolar the last decade influenced by Joseph Biederman and his minions at Harvard and Mass General. My daughter is a direct marketing target example of the bipolar paradigm medication platform gone bad. She’s disabled as a result of all of this. I appreciate anyone coming from the inside and telling these stories of corruption, especially using their abstracts and own words for proof it’s ego based, and selfishly promoted. Nemeroff and his Paxil dinners at fine restaurants across the country. What an arrogant….

    August 30, 2010 | 1:37 PM

    PS– I brought up Dalai Lama due to the Mind vs Brain….Mindfulness vs chemicals for depression is key….

    August 30, 2010 | 2:52 PM

    “and his Paxil dinners at fine restaurants across the country. What an arrogant….” You know, that’s the way I’m beginning to think of Dr. Nemeroff – not as “arrogant,” but as “an arrogant” using the adjective as a noun. I had about been able to stop writing about him until I saw this article. I looked back at his other published comments on this topic. Here’s one such comment:

    “This is where the future of psychiatry is going,” Nemeroff said. “The task before us is very large because each of these subtypes of depression is biologically distinct and will have different predictors of treatment response. But there is no doubt that what we will be able to do is end this interminable trial-and-error method that all of us are stuck with treating depressed patients.”

    I’m tired of him talking about his fantasies for the future. He has no idea that these “subtypes of depression” even exist. It’s just his new wave of the future idea for today – another breakthrough just around the corner. Yawn…

    I don’t know where Psychiatry is going myself, but with Nemeroff at the helm, it will simply go away.

    August 30, 2010 | 4:36 PM

    I am very disappointed that a perfectly good scandal was “wasted.” It should have brought Nemeroff down and finished him off. Instead, he weaseled out and now probably has an even more lucrative deal at Miami — aided and abetted by Insell and NIMH.

    August 31, 2010 | 9:36 AM

    I’m getting a sense, Mickey, for your views on the limits of reductionism but am less certain how you actually feel about Dr. Nemeroff………(note to self: remove tongue from cheek)

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