Pointer to Daniel MacArthur’s (Genomes Unzipped) post on the recent political grandstanding in consumer genetics.

This blog is more genomes, brains, social entrepreneurship and health 2.0 – than politics.   Hopefully the political phase will soon pass and some sensible regulations will preserve the right of consumers to access their genomes, while protecting consumers from scammers.

The one thing I hope does not happen is that the regulatory agencies (they work for us right?) “punt” on the issue and turn the whole consumer genetics ball of wax over to medical doctors and the medical insurance complex.  Like many, I am inspired by open-source, open-access, crowd-sourcing, bioinformatic and other open, web-based tools that allow consumers to by-pass the so-called “experts” in news media, finance, health and so many other industries that are being transformed by information technology.   The economic benefits for consumers are well documented, and so,  a country like the U.S. – economically sinking in a healthcare affordability crisis – might benefit (in the longer run) if it nurtured industries that helped consumers freely and openly ascertain their risks for illness without having to go through the economic choke point of an establishment of medical “experts”.

See health 2.0,  Regina Herzlinger’s “Who Killed Health Care?“,  Michael E. Porter and Elizabeth Olmsted Teisberg’s “Redefining Health Care: Creating Value-Based Competition on Results“,  Andy Kessler’s “The End of Medicine: How Silicon Valley (and Naked Mice) Will Reboot Your Doctor“  and Nobel Prize-winning economist Kenneth Arrow’s classic 1963 essay “Uncertainty and the Welfare Economics of Medical Care“  for some more on this.

Update:  The comment stream on Daniel MacArthur’s (Genomes Unzipped) post are chilling.  Many of the responders seem to have experience in the direct-to-consumer genetics business, and they don’t sound as optimistic as my (naive) self.  Part of one comment:

Seriously, you don’t understand. The DTC testing industry is ALREADY DEAD. In the Wall Street Journal, Shuren declared DTC subject to PMA approval, which costs tens of million of dollars! People are quitting the companies by the droves. 23andMe’s former director of regulatory affairs left for NextBio. VCs have refused to re-up. There will be no Series X+1 financing for an industry with no growth potential.

As far as science movies go, the new movie, “To Age or Not To Age” seems like a lot of fun.  The interview with Dr. Leonard Guarente suggests that the sirtuin genes play a starring role in the film.  Certainly,  an NAD+ dependent histone deacetylase – makes for a sexy movie star – especially when it is able to sense diet and metabolism and establish the overall lifespan of an organism.

One comment in the movie trailer, by Aubrey de Grey, suggests that humans may someday be able to push the physiology of aging to extreme ends.  That studies of transgenic mice over-expressing SIRT1 showed physiological properties of calorie-restricted (long lived) mice – even when fed ad libitum – suggests that something similar might be possible in humans.

Pop a pill and live it up at your local Denny’s for the next 100 years?  Sounds nice (& a lot like grad school).

Just a few twists to the plot here.  It turns out that – in the brain – SIRT1 may not function as it does in the body.  Here’s a quote from a research article “Neuronal SIRT1 regulates endocrine and behavioral responses to calorie restriction” that inactivated SIRT1 just in the brain:

Our findings suggest that CR triggers a reduction in Sirt1 activity in hypothalamic neurons governing somatotropic signaling to lower this axis, in contrast with the activation of Sirt1 by CR in many other tissues. Sirt1 may have evolved to positively regulate the somatotropic axis, as it does insulin production in β cells, to control mammalian health span and life span in an overarching way. However, the fact that Sirt1 is a positive regulator of the somatotropic axis may complicate attempts to increase murine life span by whole-body activation of this sirtuin.

To a limited extent, it seems that – in the brain – SIRT1 has the normal function of promoting aging.  Therefore, developing “pills” that are activators of SIRT1 would be good for the body, but somehow might be counteracted by what the brain would do.  Who’s in charge anyway?  Mother Nature will not make it easy to cheat her! Another paper published recently also examined the role of SIRT1 in the brain and found that – normally – SIRT1 enhances neuronal plasticity (by blocking the expression of a  micro-RNA miR-134 that binds to the mRNA of, and inhibits the translation of, synaptic plasticity proteins such as CREB).

So, I won’t be first to line up for SIRT1 “activator” pills (such as Resveratrol), but I might pop a few if I’m trying to learn something new.

The current buzz about about GWAS  and longevity and GWAS in general has stirred up many longstanding inconvenient issues that arise when trying to interpret the results of very large, expensive and worthwhile genetic studies.  Its seems that Mother Nature does not give up her secrets without a fight.

One of the most common “inconvenient issues” is the fact that so many of the SNPs that come out of these studies are located far away from protein-encoding exons.  This ubiquitous observation is almost always followed with, “well, maybe its in linkage disequilibrium with a more functional SNP” or something along these lines – wherein the authors get an automatic pass.  OK by me.

Another “inconvenient issue” is the fact that many of these SNPs are of minimal effect and don’t exactly add up or interact to account for the expected heritability.  This problem of “missing heritability” is a big one (see some new insights in the latest issue of Nature Genetics) leading many to suspect that the effects of genes are dependent on complex interactions with each other and the environment.

A recent paper, “A map of open chromatin in human pancreatic islets” [doi:10.1038/ng.530] by Gaulton and colleagues caught my eye because it seems to shed light on both of these particular inconvenient issues.  The authors find that the diabetes risk variant rs7903146 in the TCF7L2 gene is both located in an intron and subject to epigenetic regulation (our sedentary, high-fat, high-stress lives can potentially interact with the genome by causing epigenetic change).

It appears that the T-allele of the intronic rs7903146 is correlated with a more open, transcription-prone form of DNA/chromatin than is the C-allele. The authors confirmed this using both chromatin mapping and gene expression assays on pancreatic islet cells harvested from non-diabetic donors and islet cell-lines.  The results suggest that the risk-conferring T-allele of this intronic SNP may be driving expression (gain-of-function) of the TCF7L2 gene.  What types of environmental stimuli might also impact the opening and closing of chromatin at this location?

This type of interplay of environment, genome and epigenome is probably rampant in the area of brain and behavior – so perhaps the study of diabetes will provide some clues to the many GWAS SNPs that are far away from exons. More on the genetics of epigenetics here.

This post belongs to an ongoing exploration of mindfulness biology.

On February 27, 2009 a letter appeared in Science Magazine entitled, “Neuroscience and the Soul” (and covered here).   An heavy topic – even for a science journal! and much to explore down the road as the cross-informing synthesis of genetics and neuroscience continues.

As it turns out, I’m enjoying some summer reading of Jonah Lehrer‘s Proust Was A Neuroscientist and chapter 1 does not disappoint! It covers the life and poetry of Walt Whitman who was among the first modern western artists to reject dualist notions of a dichotomy between mind and body that stemmed from early Christian writings and from the philosophies of Rene Descartes (1641).  Whitman, rather,  embraced longstanding eastern notions of a synthesis and continuity of the mind and body.   Whitman’s poem, I Sing The Body Electric captures some of his youthful ardor for the human body and the human condition.  Just 2 lines from Chapter 1, line 10:

“And if the body does not do fully as much as the soul?  And if the body were not the soul, what is the soul?”

Ideas with such eastern influence earned him accolades as, “a remarkable mixture of the Bhagavad Ghita and the New York Herald” in his contemporary 1850′s press.  Lehrer also traces the birth of modern neuroscience to early pioneers such as the psychologist William James, who, it turns out, was a great admirer of Whitman’s poetry.

So it seems that the “Neuroscience and the Soul” debate continues … from a wrong turn with Descartes in the 1600′s, steered back on track by Whitman and James in the 1850′s? Where will the genome lead us?

This post is part of an ongoing exploration of  “mindfulness” biology and the neurobiology of reflecting inwardly on one’s mental life.  I hope it helps support the self-discovery aim of the blog.

In some ways, the 8 limbs of yoga described in the yoga sutras, seem a bit like a ladder, rather than a concentric set of outreached arms or spokes on a wheel.  As I practice this form of postures and mindfulness, it seems like I’m working toward something.  But what?  I certainly feel healthier, and also enjoy the satisfaction of getting slightly more able (ever so slightly) to shift into new postures – so am quite motivated to continue the pursuit.  Perhaps this is how yoga got started eons ago?   Just a pursuit that – by trial and error – left its practitioners feeling more healthy, relaxed and more in touch with their outer and inner worlds?  But where does this path lead, if anywhere?

I was intrigued by a report published in 1973 by an 8-day study carried out on the grounds of the Ravindra Nath Tagore Medical College and Hospital, Udaipur, India and subsequent letter, “The Yogic claim of voluntary control over the heart beat: an unusual demonstration” published in the American Heart Journal, Volume 86 Number 2.  Apparently, a local yogi named Yogi Satyamurti:

Yogi Satyamurti, a sparsely built man of about 60 years of age, remained confined in a small underground pit for 8 days in what according to him was a state of “Samadhi,” or deep meditation, with all bodily activity cut down to the barest minimum.

The medical researchers had the yogi’s heart and other physiological functions under constant watch via electrical recording leads, and watched as the yogi’s heart slowed down (their equipment registered a flatline) a remained so for several days.  Upon opening up the pit, the researchers found:

The Yogi was found sitting in the same posture. One of us immediately went in to examine him. He was in a stuporous condition and was very cold (oral temperature was 34.8O C) [the same temperature as the earth around him].

After a few hours, the yogi had recovered from the experience and displayed normal physiological and behavioral function – despite 8 days underground (air supposedly seeped in from the sides of the pit) with no food or human contact!

An amazing feat indeed – one that has some scientists wondering about the psychology and physiology that occurs when advanced meditators sink into (very deep) states.  John Ding-E Young and Eugene Taylor explored this in an article entitled, “Meditation as a Voluntary Hypometabolic State of Biological Estivation” published in News Physiol. Sci., Volume 13, June 1998.   They  suggest that humans have a kind of latent capacity to enter a kind of dormant or  hibernation-like state that is similar to other mammals and even certain primates.

Meditation, a wakeful hypometabolic state of parasympathetic dominance, is compared with other hypometabolic conditions, such as sleep, hypnosis, and the torpor of hibernation. We conclude that there are many analogies between the physiology of long-term meditators and hibernators across the phylogenetic scale. These analogies further reinforce the idea that plasticity of consciousness remains a key factor in successful biological adaptation.

Practice, practice, practice – towards an ability to engage a latent evolutionary adaptation? Such an adaptation – in humans – sounds hokey, but certainly an interesting idea worth exploring more in the future.

Pity the poor brain.  What a job it has!  Did you know that just to reach into a refrigerator and grab a glass of milk, involves at least 50 or so key muscles in the hand, arm and shoulder which can, in principle, lead to over 1,000,000,000,000,000 possible combinations of muscle contractions?  Just so you know, this is 1,000 times MORE contraction possibilities than there are neurons in the brain (only a mere 1,000,000,000,000 neurons).  I’m sorry brain, I’ll keep my hands out of the fridge, I promise!

To accomplish this computational feat, Rodolfo R. Llinas and Sisir Roy in their paper entitled, “The ‘prediction imperative’ as the basis for self-awareness” [doi:10.1098/rstb.2008.0309] suggest that brain has evolved a number of strategies.

For starters, the authors point out that the brain can lower the computational workload of controlling motor output by sending motor control signals in a non-continuous and pulsatile fashion.

“We see that the underlying nature of movement is not smooth and continuous as our voluntary movements overtly appear; rather, the execution of movement is a discontinuous series of muscle twitches, the periodicity of which is highly regular.”

This computational strategy has the added benefit of making it easier to bind and synchronize motor-movement signals with a constant flow of sensory input:

“a periodic control system may allow for input and output to be bound in time; in other words, this type of control system might enhance the ability of sensory inputs and descending motor command/controls to be integrated within the functioning motor apparatus as a whole.“

Another strategy is the use of memory for the purposes of prediction (actually, their paper is part of a special theme issue from the Philosophical Transactions of the Royal Society B entitled, Predictions in the brain: using our past to prepare for the future).  The authors describe the way in which neural circuits in the body and brain are inherently good at learning and storing information which makes them very good at using that information for making predictions and pre-prepared plans for what to do with expected incoming sensory inputs.  These neural mechanisms may also help reduce computational loads associated with moving and coordinating the body.  Interestingly, the authors note,

“while prediction is localized in the CNS, it is a distributed function and does not have a single location within the brain. What is the repository of predictive function? The answer lies in what we call the self, i.e. the self is the centralization of the predictive imperative.  The self is not born out of the realm of consciousness—only the noticing of it is (i.e. self-awareness).”  Here’s a link to Llinas’ book on where the “self” resides.

Lastly, the authors suggest that the genome might encode certain structural and functional aspects of neural development that create a bias for certain types of computation and prime neural networks with a Bayesian type of prior knowledge.  Their idea is akin to an organism being “experience expectant” rather than a pure blank slate that has to learn every stimulus-response contingency by trial-and-error.  To support their notion of the role of the genome, the authors cite a 2003 study from the Yonas Lab on the development of depth perception.  Another related study is covered here.

Methinks that genetic variants might someday be understood in terms of how they bias computational processes.  Something to shoot for in the decades to come!

pointer to the NOVA program on epigenetics “Ghost in Your Genes” (YouTube link here).  Fantastic footage.  Great intro to epigenetics and so-called trans-generational effects and the inheritance of epigenetic marks – which, in some cases – are left by adverse or stressful experience.  A weird, wild, game-changing concept indeed – that my grandchildren could inherit epigenetic changes induced in my genome by adverse experience.

just a pointer to: Genetic Future’s pointer to the recent article, “Family become first to have DNA sequenced for non-medical reasons“.    The father suggests, “it will be ethically improper if you don’t have your children sequenced“.

Early days.

“Hey Dad, look at the little bwain!”  (my 4 y.o.)

In an earlier post on Williams Syndrome, we delved into the notion that sometimes a genetic variant can lead to enhanced function – such as certain social behaviors in the case of WS.  A mechanism that is thought to underlie this phenomenon has to do with the way in which information processing in the brain is widely distributed and that sometimes a gene variant can impact one processing pathway, while leaving another pathway intact, or even upregulated.  In the case of Williams Syndrome a relatively intact ventral stream (“what”) processing but disrupted dorsal stream (“where”) processing leads to weaker projections to the frontal cortex and amygdala which may facilitate gregarious and prosocial (a lack of fear and inhibition) behavior.  Other developmental disabilities may differentially disrupt these 2 visual information processing pathways.  For instance, developmental dyspraxia contrasts with WS as it differentially disrupts the ventral stream processing pathway.

A recent paper by Woodcock and colleagues in their article, “Dorsal and ventral stream mediated visual processing in genetic subtypes of Prader–Willi syndrome” [doi:10.1016/j.neuropsychologia.2008.09.019] ask how another developmental disability – Prader-Willi syndrome – might differentially influence the development of these information processing pathways.  PWS arises from the lack of expression (via deletion or uniparental disomy) of a cluster of paternally expressed genes in the 15q11-13 region (normally the gene on the maternally inherited chromosome is silent, or imprinted – related post here).  By comparing PWS children to matched controls, the team reports evidence showing that PWS children who carry the deletion are slightly more impaired in a task that depends on the dorsal “where” pathway whilst some sparing or relative strength in the ventral “what” pathway.