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NIMH and its Biologic Emphasis

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Recently (10 December 2012), NIMH director Thomas Insel wrote in his Director's blog about the top 10 advances in mental health for 2012.   Almost all were biological advances, and I wanted to react to some of those advances and think about the social determinants of mental health and the social brain hypothesis.   This is timely given the killings of young children in Connecticut and the drive to look inside people to find the sources of violence, when the sources quite probably lie outside the person in the social structures of our society.   I think of people like Adam Lanza as canaries in our social mine who alert us to the imbalances of our culture.   The American Psychiatric Association has commendably commented that mental illness is not a predictor of violence and that the mentally ill are no more likely to commit violent acts than anyone else.   Other scholars have written about our lack of capacity to predict in advance who will be violent.   The problem is where we put our focus.   Instead of focusing on the individual level, we need to focus on the social level, on the violence that we tolerate in our society.   When I was recently in Arizona, I learned that the lawmakers there wanted to solve the problem by arming teachers and principals with guns.   This seemed like such a bizarre response that could only make the problem worse by bringing more guns into the picture when we already have too many guns in circulation (89 per 100 people making us the most armed nation in the world by far).  


In The Master and his Emissary, Iain McGilchrist presents the idea that we are gradually being colonized through the left hemisphere's preference for, broadly, familiar, non-living and measurable things that can be used for instrumental purposes. As a society, we are gradually losing touch with what Iain calls "sources of intuitive life', as our societies become a virtual "hall of mirrors' in which that which is re-presented is ubiquitous, and that which is genuinely unique has less air to breathe. This response is typified in our desire to measure and assess and predict precisely who will be violent, rather than reflect upon our violent tendencies as a culture and upon our rage.   We want to identify and sequester the violent through violent means, which seems to me to be a paradox that can never work.   We continue to produce progressively more graphic and violent videogames for our children to watch and absorb, more violent movies and stories for them to consume, and then we are surprised when some of them act violent.   Traditional elders and neuroscientists around the world tell us that we absorb and are influenced by all the stories we hear and see.   These stories change us to become more like them.   Stories are not innocuous, they change us.   Therefore, we have a responsibility to tell good stories that make us better people -- more kind, more like what we imagine it means to be human.


In 2004, Dr. Steve Sussman and colleagues at the University of Southern California published a paper on the prediction of violence in adulthood among high-risk adolescents. Hard drug use, the belief that hurting another's property while drunk was acceptable, and high-risk group self-identification predicted later violence perpetration independent of baseline violence perpetration.   Mental illness was not part of the picture.   These behaviors and beliefs are more under social control than arising de novo from biology.


Here are some of Dr. Insel's exciting discoveries of 2012:


Number 10 on his list was "manipulating the epigenome to treat brain disorders".   I have written previously on epigenetics -- the science of how experience changes the way that genes are transcribed, changing what a gene does or when it does something or where it does something.   Epigenetics is indeed fascinating and speaks to the ways in which our ancestors' experiences are passed to us.   Li-Huei Tsai's research group showed that an increase in histone deacetylase 2 (HDAC2) -- a protein that plays an important role in regulating the transcription of genes which is an important part of epigenetics -- was found to reduce memory in mice (and was associated with Alzheimer's Disease in humans). Reducing HDAC2 improved memory in mice, suggesting a new target for developing treatments. 1    What is remarkable about Director Insel's interpretation is the emphasis on the search for drugs that will do this instead of reflecting upon social environments that will affect epigenetics.   I am certainly not opposed to drug development and to the creation of more effective drugs, but I am saddened by how much we avoid reflecting upon the effect that changing our social experiences and our social milieu would have on the epigenome and upon mental illness.   We just don't go there as a society.

Insel's eighth most important research was in neurodevelopmental genomics -- the search for genetic variation associated with autism spectrum disorder, schizophrenia, and bipolar disorder. 2, 3      He noted that the importance of de novo , or spontaneous mutations became more apparent in 2012. The role of paternal age in increasing the incidence these conditions demonstrated a mechanism by which environment and genes may interact. 4     State and Sestan summed up the findings in two catchy phrases: "one to many" in which each genetic finding appears to be a risk factor for several different neurodevelopmental disorders and "many to one"   in which disorders like autism appear to have perhaps hundreds of genetic factors contributing risk. 3

Insel's fourth area was " Mapping the human connectome " or the wiring diagram of the human brain, which is extremely complex. Using a new approach for visualizing white matter (the "cables" that connect brain regions), Wedeen and colleagues at Massachusetts General Hospital discovered an inherent grid pattern in the human brain. 5 While there is still discussion about the validity of this grid, the human connectome -- the comprehensive map of all neural connections in the brain -- promises to him to reveal important aspects of human variation, just as is the case with the human genome.   The social brain hypothesis suggests that this connectome is formed by our social experience and that infinite variation will exist among individuals in their neural connections.

Insel's third area was " Unexpected variation " .   This is the finding that genes can mutate in the brain after conception and can contribute toward neurodevelopmental disorders.   The world of brain science and human behavior becomes increasingly complex. 6,7   We learned that women can carry cells in their brains with DNA from their offspring.   The term microchimerism refers to the presence of male cells in a woman's cortex, which gives an entirely new meaning to the biology of motherhood. 8   We also learned that microDNA segments could be transmitted independently of chromosomes with thousands of short (200 -- 400 bases long) circular DNA elements being found that function free of the well-known structured bundles of DNA called chromosomes in mammalian cells. 9    The implications of these findings remain to be realized.

Second most interesting to Insel was "The 1000 Genomes Project", a project to sequence the genomes of 1000 typical humans, has forever put to bed the concept of "normal." The data from the first 185 volunteers has shown that the range of variation among people is stunning. Each of us has 100 genetic variants causing some loss of function, with 20 of these being variants that totally inactivate the gene. That means that each of us, on average, has a "knockout" of 20 genes. Overall, the team found more than 1000 different genes knocked out within the sample, apparently without consequences since all of their participants were selected because they were "healthy." 10 This suggests that a tremendous amount of unexpected redundancy is built into our genome. In another recent report, the 1000 Genomes Project demonstrates much of this variation is related to ancestry, with large differences observed across 14 different human populations. 11

Insel's number one exciting event of the scientific year was the results of the ENCyclopedia Of DNA Elements (ENCODE) project, which set out to map the active parts of the human genome. The prevailing belief has been that 2 percent of the genome was genes and 98 percent was "junk DNA".   It turns out that 80 percent, not 2 percent, of the genome was transcribed with over 20,000 non-coding RNA sequences serving as active biological elements of the genome. 12 He said, "The biggest finding of the year is also the most humbling: we are still in the earliest stages of understanding the blueprints that make us human."   So much that we don't know.

Of course, brain science is fascinating and it will receive the lion's share of the research funding from NIMH.   But the goal is ultimately better living through chemistry, which I don't think will work.   What we are not considering is the social brain -- how our relationships restructure our brains and control and regulate our behavior.    I think mental illness will disappear far more quickly if we attend to our social world ahead of our biology.   Of course it's interesting to know how the social world alters our biology and science deserves funding.   But, if we are interested in improving the lives of people, we must change their social milieu.   Our pet project -- building narrative competence for people with psychosis -- has little chance of being funded by NIMH (though we are applying).   It's not biologic though we believe it alters the frontal lobe and hope to find collaborators with fMRI machines to demonstrate this.   More importantly, improving people's capacity to tell good stories about their experiences helps them to function better and to live in a storied world with other storied people with less friction and more ease.


  1 Gräff J, Rei D, Guan JS, Wang WY, et al. An epigenetic blockade of cognitive functions in the neurodegenerating brain. Nature. 2012 Feb 29;483(7388):222-6. PMID: 22388814

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Lewis Mehl-Madrona graduated from Stanford University School of Medicine and completed residencies in family medicine and in psychiatry at the University of Vermont. He is the author of Coyote Medicine, Coyote Healing, Coyote Wisdom, and (more...)

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