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Posts Tagged ‘Health’

Lonely child
Image by kodomut via Flickr

For humans, there are few sights more heart-wrenching than an orphaned child (or any orphaned vertebrate for that matter).  Isolated, cold, unprotected, vulnerable – what could the cold, hard calculus of natural selection – “red in tooth and claw” – possibly have to offer these poor, vulnerable unfortunates?

So I wondered while reading, “Functional CRH variation increases stress-induced alcohol consumption in primates” [doi:10.1073/pnas.0902863106].  In this paper, the authors considered the role of a C-to-T change at position -248 in the promoter of the corticotropin releasing hormone (CRH or CRF) gene.  Its biochemical role was examined using nuclear extracts from hypothalamic cells, to demonstrate that this C-to-T nucleotide change disrupts protein-DNA binding, and, using transcriptional reporter assays, that the T-allele showed higher levels of transcription after forskolin stimulation.  Presumably, biochemical differences conferred by the T-allele can have a physiological role and alter the wider functionality of the hypothalamic-pituitary-axis (HPA axis), in which the CRH gene plays a critical role.

The authors ask whether primates (rhesus macaques) who differ in genotype (CC vs. CT) show any differences in physiological stress reactivity – as predicted by differences in the activity of the CRH promoter.  As a stressor, the team used a form of brief separation stress and found that there were no differences in HPA function (assessed by ACTH and Cortisol levels) in animals who were reared by their mothers.  However, when the stress paradigm was performed on animals who were reared without a mother (access to play with other age-matched macaques) there were significant differences in HPA function between the 2 genetic groups (T-alleles showing greater release of stress hormones).  Further behavioral assessments found that the peer reared animals who carried the T-allele explored their environment less when socially separated as adults (again no C vs. T differences in maternally reared animals).  In a separate assessment the T-carriers showed a preference for sweetened alcohol vs. sweetened water in ad lib consumption.

One way of summarizing these findings, could be to say that having no mother is a bad thing (more stress reactivity) and having the T-allele just makes it worse!  Another way could be to say that the T-allele enhances the self-protection behaviors (less exploration could be advantageous in the wild?) that arise from being orphaned.  Did mother nature (aka. natural selection) provide the macaque with a boost of self-preservation (in the form of a T-allele that enhances emotional/behavioral inhibition)?  I’m not sure, but it will be fun to report on further explorations of this query.  Click here for an interview with the corresponding author, Dr. Christina Barr.

—p.s.—

The authors touch on previous studies (here and here) that explored natural selection on this gene in primates and point out that humans and macaques both have 2 major haplotype clades (perhaps have been maintained in a yin-yang sort of fashion over the course of primate evolution) and that humans have a C-to-T change (rs28364015) which would correspond to position -201 in the macaque (position 68804715 on macaque chr. 8), which could be readily tested for similar functionality in humans.  In any case, the T-allele is rare in macaques, so it may be the case that few orphaned macaques ever endure the full T-allele experience.  In humans, the T-allele at rs28364015 seems more common.

Nevertheless, this is yet another – complicated – story of how genome variation is not destiny, but rather a potentiator or life experience – for better or worse.  Related posts on genes and early development (MAOA-here), (DAT-here), (RGS2-here), or just click the “development tag“.

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The hydrophobic cell membrane prevents charged...
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Few genes have been studies as intensely as apolipoprotein E (APOE).  In particular, one of its variants, the epsilon-4 allele has been especially scrutinized because it is correlated with an earlier onset (about 10 years earlier than average) of Alzheimer’s Disease.  Among the many roles of APOE – its just a tiny cholesterol binding protein – are those as participant in synaptic plasticity, early neural development, damage-response and other processes – all of which share the need for the synthesis and movement of neuronal membranes (see the fluid mosaic model) and their component parts – such as cholesterol.   Hence, whenever neural membranes are being synthesized (plasticity & development) or damaged (overstimulation and other sources of oxidative damage) the tiny APOE is there to help with its membrane stabilizing cholesterol molecule in hand. Over the course of a lifetime, routine damage to neuronal membranes adds up (particularly in the hippocampus where constant storage-recall memory functions place enormous demands on synaptic plasticity systems), and individuals (such as epsilon-4 carriers) may simply show more wear-and-tear because their version of APOE is not as optimal as the other forms (epsilon-2 and -3).

apoeWith this etiological model in mind, perhaps you would like to take better care of you cell membranes (much like your car mechanic implores to change your car’s spark plugs and oil to keep the engine clean on the inside).  Moreover, perhaps you would like to do-so especially if you knew that your APOE system was less optimal than average.  Indeed, results from the recent REVEAL study suggest that folks who are in their 50’s are not unduly distressed to make this genetic inquiry and find out their genotypic status at this APOE polymorphism – even though those who discovered that they were epsion-4 carriers reported more negative feelings, understandably.  Still, with a number of education and intervention strategies available, an optimistic outlook can prevail.

Furthermore, there are ever newer diagnostic strategies that can improve the rather weak predictive power of the genetic test.  For example, cognitive assessments that measure hippocampal-dependent aspects of memory or visual orienting have been shown to be valid predictors of subsequent dementia – even moreso in populations that carry the APOE epsilon-4 allele.  Other forms of neuroimaging that directly measure the structure and function of the hippocampus also have tremendous sensitivity (here for a broad review of imaging-genetics of AD) and can, in principle, provide a more predictive view into one’s distant future.

On the very cutting edge of this imaging-genetic crystal ball technology, lies a recent paper entitled, “Distinct patterns of brain activity in young carriers of the APOE-e4 allele” by Fillippini and colleagues [doi: 10.1073/pnas.0811879106].  Here, the research team asks whether individuals in their late 20’s show structural/functional brain differences that are related to APOE genotype.  They employ various forms of imaging analysis such as a comparison of brain activity when subjects were performing a novel vs. familiar memory task and also an analysis of so-called resting state networks – which reflect a form of temporal coherence (brain areas that oscillate in-sync with each other when subjects are lying still and doing nothing in the scanner).  For the analysis of the memory task, the team found that APOEe4 carriers showed more activation in the hippocampus as well as other brain regions like the anterior midbrain and cerebellum.  When the team analysed a particular resting state network – the default mode network – they found differences in the medial temporal lobe (containing head of the hippocampus and amygdala) as well as the medial prefronal cortex.  According to the paper, none of these differences could be explained by differences in the structure or resting perfusion of the young-adult brains in the study.

Wow, these results seem to suggest that decades before any mild cognitive impairments are observable, there are already subtle differences in the physiology of the APOEe4 brain – all of which could be detected using the data obtained in 6 minutes of rest. 6 minutes of rest and spit in a cup – what does the future hold?

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A statue of Asclepius. The Glypotek, Copenhagen.
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My wife was recently unfortunate to spill hot soup on her hand and ended up with a pretty uncomfortable set of 2nd degree burns. At our fingertips (mine anyway) we had easy online access to guidelines for pain management and infection prevention. The next day at work, she was able to see a company-sponsored nurse practitioner who cleaned, redressed and provided a prescription for burn cream. Only after the smoke cleared (or soup as it were) did we realize she was going to be OK and that we had paid $0 so far with a $10 co-pay coming for the burn cream. At dinner that night (we stuck with cold chicken salad) we each wondered uneasily whether we should have, or should think of, going to see a doctor. “Wouldn’t that be best?” “But you seem to have gotten such good care already.” The conundrum reminded me of Andy Kessler‘s book, The End of Medicine, where he becomes a human guinea pig and explores all sorts of medical diagnostics technology and also wonders how much longer people will really need doctors. We’re not as brave as Mr. Kessler, but are certainly wondering how far the consumer revolution can go in healthcare. For the time being, no more soup.

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In, The New Financial Order, professor Robert Shiller offers an in-depth analysis of how finance can and should be used to improve the human condition. By appropriately adapting financial instruments with risk, the consequences of many of life’s sudden shocks (natural disaster, loss of job, health crisis etc.) are readily ameliorated. Although he does not cover health insurance directly, his suggestions on how to better manage other types of risk point to an alternative viewpoint … away from the polarized “universal coverage” vs. “consumer-driven private coverage” debate. New bioinformatic strategies for managing health risk could readily be linked to financial instruments that more efficiently provide buffering to the economic consequences of illness.

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