just a pointer to: Madness & Modernity: Mental illness and the visual arts in Vienna 1900
“Vienna in 1900 was a city obsessed with the mind. Political unrest had left the Viennese with an overwhelming sense that they were living in ‘nervous times’.”
Sounds like the media scene today.
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Posted in Uncategorized | Tagged Art | Leave a Comment »
… caught this related video on the same topic on July 24th.
The core issues of government transparency and consumer protection seem to apply to healthcare reform as well. How best can the government protect consumers ? paternalistic behavior or transparency ?
Posted in Uncategorized | Tagged comics, economics | Leave a Comment »
One way to organize the great and growing body of research into autism is via a sort-of ‘top-down’ vs. ‘bottom-up’ perspective. From the ‘top-down’ one can read observational research that carefully catalogs the many & varied social and cognitive attributes that are associated with autism. Often times, these behavioral studies are coupled with neurochemical or neuroimaging studies that test whether variation in such biomarkers is correlated with aspects of autism. In this manner, the research aims to dig down into the physiology and biochemistry of the developing brain to find out what is different and what differences might predict the onset of autistic traits. At the deepest biological level – the bedrock, so to speak – are a number of genetic variations that have been correlated with autism. These genetic variants permit another research strategy – a ‘bottom-up’ strategy that allows investigators to ask, “what goes wrong when we manipulate this genetic variant?” While proponents of each strategy are painfully aware of the limitations of their own strategy – oft on the barbed-end of commentary from the other side – it is especially exciting when the ‘top-down’ and ‘bottom-up’ methods find themselves meeting in the agreement in the middle.
So is the case with Nakatani et al., “Abnormal Behavior in a Chromosome- Engineered Mouse Model for Human 15q11-13 Duplication Seen in Autism” [doi: 10.1016/j.cell.2009.04.024] who created a mouse that carries a 6.3 megabase duplication of a region in the mouse that luckily happens to be remarkably conserved in terms of gene identity and order with the 15q11-13 region in humans – a region that, when duplicated, is found in about 5% of cases with autism. [click here for maps of mouse human synteny/homology on human chr15] Thus the team was able to engineer mice with the duplication and ask, “what goes wrong?” and “does it resemble autism in any kind of meaningful way (afterall these are mice we’re dealing with)?”
Well, the results are rather astounding to me. Most amazing is the expression of a small nucleoar RNA (snoRNA) – SNORD115 (mouse-HBII52) – that function in the nucleolus of the cell, and plays a role in the alternative splicing of exon Vb of the 5HT2C receptor. The team then found that the editing of 5HTR2C was altered in the duplication mice and also that Ca++ signalling was increased when the 5HTR2C receptors were stimulated in the duplication mice (compared to controls). Thus, a role for altered serotonin function – which has been a longstanding finding in the ‘topdown’ approach – was met midway and affirmed by this ‘bottom-up’ approach! Also included in the paper are descriptions of the abberant social behaviors of the mice via a 3-chambered social interaction test where duplication mice were rather indifferent to a stranger mouse (wild-type mice often will hang out with each other).
Amazing stuff!
Another twist to the story is the way in which the 15q11-13 region displays a phenomenon known as genomic-imprinting, whereby only the mother or the father’s portion of the chromosome is expressed. For example, the authors show that the mouse duplication is ‘maternally imprinted’ meaning that that pups do not express the copy of the duplication that comes from the mother (its expression is shut down via epigenetic mechanisms that involve – wait for it – snoRNAs!) so the effects that they report are only from mice who obtained the duplication from their fathers. So, if you by chance were wondering why its so tough to sort out the genetic basis of autism – here’s one reason why. On top of this, the 5HTR2C gene is located on the X-chromosome which complicates the story even more in terms of sorting out the inheritance of the disorder.
Further weird & wild is the fact that the UBE3A gene (paternally imprinted) and the genetic cause of Angelman Syndrome sits in this region – as does the SNRPN gene (maternally imprinted) which encodes a protein that influences alternative RNA splicing and also gives rise to Prader-Willi syndrome. Thus, this tiny region of the genome, which carries so-called “small” RNAs can influence a multitude of developmental disabilities. Certainly, a region of the genome that merits further study!!
Posted in 5HTT, SNORD115, SNRPN, UBE3A | Tagged Angelman Syndrome, autism, Biology, Development, Epigenetics, Eukaryotic, Gene, Genetics, Genomic imprinting, Prader-Willi syndrome, RNA | 1 Comment »
Very much enjoyed Professor & Blogger Tyler Cowen’s new book. He muses on the deep seated joy that people have in self-ordering information and the economic value that comes from facilitating this natural instinct. As a blogger-in-training, the book has really helped me better understand how a blog might fit into existing value-chains within the world of homo-economicus who, according to Professor Cowen, is using social media to become more entrepreneurial and humane. Its easy to imagine how folks may try and self-order their genome information in the years to come. I hope I can help facilitate this by sharing my own enthusiasm and experience as an early adopter. If you want your assumptions on human behavior to be shaken up in a good way – read this book!
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While often the object of scorn from its capitalistic southern neighbor, the Canada Foundation for Innovation has just awarded Dr. David Kennedy a large research grant to deploy both neuroimaging and genetic markers in the development of personalised treatment for schizophrenia – through a program dubbed “neuroIMAGENE“. Dr. Kennedy suggests that this technological strategy may actually save money in the long run by helping physicians select the proper medication and dosage.
Capitalistic scorn huh? This news comes as the U.S. healthcare flagship GE healthcare flushes its own personalized medicine effort all the while nary a Canadian bank requires bailout largesse. Indeed.
Posted in Uncategorized | Tagged Genetic testing, Personalized medicine, schizophrenia | Leave a Comment »
Was bummed to hear Nick Haymenn say (download & listen to minute 10 on this Bloomberg News podcast) that GE healthcare has abandoned its molecular & imaging diagnostics program aimed at early detection and intervention.
Crap, that sets things back quite a bit across the medical universe I suspect.
Posted in Uncategorized | Tagged economics, Personalized medicine | Leave a Comment »
pointer to David Healy’s lecture, “The Future of Medical Care: Can Industrialized and Marketized Healthcare be Made Universally Available?” I enjoyed this very much. He places the notion of “caring” and “doing no harm” as a top priority in medicine (his focus is largely on psychiatric care) and then lays out a way for this old fashioned value to fit within the large-scale science-driven, evidence-based healthcare system of today (mainly by adequately considering the side-effects of medication treatment). Dr. Healy is well known for taking the pharma industry to task for selective-presentation of data, ghost-writing and other aspects of profiteering behavior – and does not disappoint here.
As a personal observation, I often hear psychiatrists and researchers say that, “Schizophrenia is (someday will be classified into) 10 separate disorders” – which, after listening to Dr. Healy’s lecture, seems like code for, “if we increase the complexity of the diagnostic criteria, we can create more separate avenues for treatment”, which seems like code for, “we can pull in more revenue“. Perhaps systems neuroscience (perhaps even genetics?) will reveal that there are many common networks that are disrupted across disorders and might help counteract additional splintering of diagnostic criteria. I don’t know, but certainly an issue worth exploring in more detail.
UPDATE: Here’s an example of common genetic variation that accounts for risk of both Schizophrenia and Bipolar Disorder. The current head of the NIMH says, “These new results recommend a fresh look at our diagnostic categories” Nice to see this!
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Just feeling inspired by this short interview with Tyler Cowen. I share his feeling that blogging is mainly just a way to share your enthusiasm … but certainly would be nice to have Professor Cowen’s brain power on top of the enthusiasm!
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pointer to Jonah Lehrer’s post on the neurobiology of Swoopo, the auction site where you purchase a “bid” for $0.60 and then swoop in at the last second to outbid rivals by a mere $0.02 – until they swoop back in and outbid you back – ad infinitum. I tried Swoopo, and found it tedious and maddening – so clearly rigged to bleed its poor bidders dry $0.60 at a time (you have to buy bids in blocks of $24 or more). One could (and some do) rashly sink tens or hundreds of dollars into the process of bidding and then walk away with nothing. There are known to be genetic influences on an individual’s sensitivity to the magnitude of immediate vs. delayed rewards (sure some people do win a $1,300 macbook for $250 which can raise one’s expectations of such a sweet reward) but it seems Swoopo is geared to folks on the extreme right tail of the distribution here. Like most, I’d rather be outbid on ebay and salve my bruised dignity with the money I didn’t blow on a netbook computer I didn’t really need.
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Yesterday, there were some grumblings on the nomination of Francis Collins to the head of NIH. Some folks feel that the genome-wide, genome-everything approach to medicine has somewhat over-promised and under-delivered in its promise to elucidate the molecular pathways of human disease. In the field of mental health, the whole-genome era is just now dawning and ever more, ever larger studies are reporting the results of GWAS and other global sweeps for genetic risk. So, its fair to ask whether the whole-genome approach hath bourne the promised fruit. Exactly, how much of the overall risk of illness can we account for using the present genetic knowledge? I’d like to know & will be working to track this “bottom line” statistic in the future.
However, I suspect that the numbers may be humbling. In part, because of the tricky ways in which the genome interacts with the pre- & post-natal environment during development. For example, consider the recent paper by Saijo et al. “A Nurr1/CoREST Pathway in Microglia and Astrocytes Protects Dopaminergic Neurons from Inflammation-Induced Death” [doi 10.1016/j.cell.2009.01.038]. Here the team considers neurodegenerative processes and how the tissues of the brain cope with unwanted oxidative pro-inflammatory damage. Specifically, the team shows that Nurr1, a so-called orphan nuclear receptor that is known to regulate the development of midbrain dopamine neurons, actually has another function – one that occurs inside the microglia of the brain (special macrophage-like cells of the brain that can clear infection – ideally without harming surrounding neural circuitry). The team injected (into the midbrain) an evil, bacteria-like, oxidative sludge known as lipopolysaccharide (LPS) which triggers a full-blown immunologic alarm that often has the unwanted side-effect of inducing the death of dopaminergic neurons. This is very BAD – as it creates a Parkinsonian condition – but, nevertheless is something that our bodies and brain must cope with throughout our life-cycle since we’re always being exposed to bacteria and other pathogens. The team finds that the cytotoxic response of microglia is repressed by Nurr1 such that when Nurr1 expression is blocked, the microglia are more active and then, unfortunately, cause more collateral damage to the dopaminergic cells in their efforts to clear the LPS. So it seems that Nurr1 helps to save dopaminergic neurons by dampening down the normal inflammation response systems that – when faced with foreign infections – can cause collateral damage in their efforts to clear the infection. Wow, so Nurr1 helps to give birth to dopamine neurons and to keep them safe from harm. Such a gene, is one I’d hope would work well. Not surprisingly, mutations in Nurr1 have been associated with the risk of Parkinson’s Disease.
More interestingly, the way in which Nurr1 seems to carry out its regulation of this very common type of gene-x-environment (infection) interaction is through a so-called CoREST repressor complex which is implicated in various epigenetic forms of gene regulation – which can have long-lasting effects on cells, perhaps long-after the infection has cleared.
Thus, just this one story around little, itty bitty DNA binding factor Nurr1, who, alone can’t account for more than a hair’s worth of genetic risk, may, in fact, play a critical role in the onset of complex mental illness. It would seem perhaps that identifying genetic risk factors may only be the beginning of a long, complex search for the biological roots of mental disability – where genes and environment weave intractable tales.
Posted in NURR1 | Tagged Dopamine, Epigenetics | 1 Comment »
pointer to Mark Henderson’s coverage of how the British NHS may adapt to the rise of direct-to-consumer genetic testing. Among the complexities mentioned were its ubiquity, potential (yet mostly future) benefits and costs of retraining and implementing. Also, tighter regulatory standards for DTC vendors.
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Back in the day, when the fam would get together at my parents’ house, I would enjoy shuffling through their box of old photos. Looking at childhood pictures of myself and relatives, it was natural to compare our adult selves to the old pictures and look for similarities – emotional expressions, gestures, etc. – that have carried on through the years and are (were) a part of who we are (became) today. It’s always amazing what you think you can see, and if you’re like me, you may be somewhat amazed by how much of your adult self was already in full swing as a child. The manner in which the developing brain confers such stability over time and over generations (now I see my own childhood traits in my son – yikes!) is of course a timeworn question among families and scientists alike.
That the genome would contribute to cross generational parent-child similarities in personality and temperament is fairly obvious, but not so apparent is how the genome interacts with the environment to exert an influence on psychological development. Along this line of inquiry, a research article entitled, “Influence of RGS2 on anxiety-related temperament, personality, and brain function” by Smoller and colleagues [free access] provides an amazing perspective – from a single gene. RGS2, eponymously named as a regulator of G-protein signaling, was first identified as a factor that regulates emotional behavior in mice [PMID] and subsequently as a risk factor for schizophrenia [PMID] as well as anxiety disorders in humans [PMID]. In the current study, the team examined the temperament of children (119 families), personality of adults (744 undergraduates) and brain activity in adults (55 participants) to ascertain whether the adult risk for anxiety conferred by RGS2 might be related to actions of the gene that occur much earlier in development – such as on the systems that regulate temperament in children. Specifically, they focused on behavioral inhibition in children (shy, avoidant, restrained in novel situations) and introversion in adults – as these traits have been associated with increased risk for anxiety disorders.
What is so interesting to me is that RGS2 (particularly the G allele of the 3’UTR SNP rs4606) was found to be associated with both childhood temperament and adult personality. Thus, an introverted adult who looks through an old photo album and sees themselves to have been a shy or inhibited child, may be experiencing – to a small degree – the effects of the RGS2 gene. The team suggests, via additional brain imaging-genetic studies, that RGS2 is of particular relevance to activity in circuits containing the insular cortex and amygdala – when subjects perform an emotional face matching task.
My own 23andme record does not contain the rs4606 SNP but does contain the data for rs1819741 where a T allele was significantly associated with introversion. Since I’m a C/T heterozygote, I guess I’ll have to look a bit harder at my old pictures to see signs of behavioral inhibition.
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Posted in Amygdala, Insula, RGS2 | Tagged 23andMe, Anxiety, Development | 1 Comment »
Just discovered FORA.tv media channel – happened on this discussion with Joe Pantoliano on his advocacy for mental illness.
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Amidst the steady stream of basic imaging and genetic science that pours forth into the literature each day (or in response to Eric Kandel‘s latest update on the state of brain science and mental health), how could anyone remain glum? In Hamlet, the King asks, “How is it that the clouds still hang on you?” to which Hamlet replies, “Not so, my lord, I am too much in the sun“. So it seems the case with John M. Grohol, whose recent article, “Chasing the Genetic Ghosts of Mental Illness” which rightly maintains an evenly skeptical long-term perspective on the (as-yet-unrealized-over) promise of genetic and brain imaging research. Certainly, patients may be encouraged by new findings, but as Grohol points out, there is a notorious 1-step forward, 2-steps back dynamic to basic research that can undermine the time-line of promise delivery. Indeed, from a patient’s perspective, basic research that characterizes empirical therapeutic effects may only deliver marginal benefits at best. Thus, there may be some need to better communicate on the fruits of basic research now – abundant or sparse as they may be. I will keep Grohol’s perspective in mind.
Posted in Uncategorized | Tagged Functional magnetic resonance imaging, Genetic testing | 1 Comment »
The basic helix-loop-helix transcription factor, neurogenin-1 is known to regulate neural development and neurite outgrowth. As such, it makes for a particularly interesting point to begin to understand mental illness and its complex developmental origins. The recent paper by Ho et al., “Basic helix–loop–helix transcription factor NEUROG1 and schizophrenia: Effects on illness susceptibility, MRI brain morphometry and cognitive abilities ” [doi: 10.1016/l.schres.2008.08.009] makes for a very interesting read since this gene resides in the midst of the chromosome 5q31 region – which has been a risk hotspot in a number of previous linkage studies – and – two snps in NEUROG1 (the C-allele of rs2344484 and the G-allele of rs8192558) have also been associated with the disorder.
The authors report that in a sample of 392 patients and 226 control subjects, the major alleles of rs2344484 and rs8192558 were more prevalent among patients. Furthermore, some of the participants underwent structural MR brain imaging which allowed the research team to examine where in the brain such genetic risk might arise from. Interestingly, the team found that both patients and control subjects who carried the C-allele of rs2344484 showed somewhat smaller volumes of grey matter. For example, in Table 3 there were 145 CC,CT individuals with an average of 662 cubic centimeters of grey matter while the 28 participants with the TT genotype showed an average volume of 682 cu.cm. This allele was also found to be associated with poorer cognitive abilities in these C-carrier participants.
As pointed out by the research team, NEUROG1 is expressed early in the development of the human brain and is implicated in the differentiation of cortical progenitor cells and of glutamatergic excitatory cells in deep layers of the cortex. Thus, the role of variation in a transcription factor – a gene that regulates the expression of other genes – in the risk of schizophrenia can be very early and with very broadly effects on the neocortex.
How to treat such an early deficit? Would be interesting to discuss further. My own 23andMe profile shows a CT heterozygote which places me within the higher risk, but more common genotypic pool. Hmmm. What to make of that?
Posted in NEUROG1 | Tagged 23andMe, Mental disorder, schizophrenia | Leave a Comment »
pointer to — Financial analyst Andy Kessler’s recent article “Technology Review: A Pound of Cure” discusses whether several $billion of government incentives for digitizing health information is enough to root out inefficiencies in a $2.4 trillion industry. Not if hospitals have any say, suggests Kessler. However, the long-run prospects of digitizing should help eventually wring inefficiency out of the system.
I’ve enjoyed his previous books on finance and very much enjoyed his keen financial analyst insights into healthcare in “The End of Medicine: How Silicon Valley (and Naked Mice) Will Reboot Your Doctor“.
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pointer to — Dr. John Grohol, the CEO and founder of Psych Central, has a great post “You have the right to your health data” and introduces the Declaration of Health Data Rights, a simple statement of fundamental patient rights. Check it out and endorse!
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Just a pointer to an amazing analysis on the politics of moving forward with a more comprehensive government sponsored healthcare option. Sadly, but not surprisingly, the flow of lobbying funds predicts who will vote to maintain the status quo.
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Just a pointer to a new step-by-step guide video showing Promethease in action – nice!
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Genes 2 Brains 2 Mind 2 Me 