Saccharomyces boulardii improves migration of new epithelial cells

The lifespan of healthy intestinal epithelia is generally accepted to be about 5 days.  These cells, once departed and sloughed off into the fecal stream, are replaced by newer, younger, healthier cells which proceed through the same life-cycle.  In the case of inflammatory bowel diseases (IBDs), in addition to inflammation/ulceration/tissue injury, the migration process of these new epithelial cells is stunted.  Since the replacement cells have trouble reaching their destination, damage to the intestinal lining is exacerbated.

A recent study -- published in PLoS ONE and open access if anyone wants to take a peek -- investigated the capacity of a nonpathogenic yeast to alleviate this stunted migration of new epithelial cells to the tips of intestinal villi (the fingers of tissue that protrude from the intestinal wall to create surface area for absorption).  Saccharomyces boulardii (Sb) is typically used to treat issues such as diarrhea, the idea being that it stimulates growth factors that help restore homeostasis to the gut.

This nigh-rockstar study strikes me because it is targeting a curative mechanism as opposed to a squelching of symptoms.  To achieve actual remission in IBDs, one has to pwn both inflammatory and repair dysfunctions.  The inflammatory component is predominantly targeted by the entourage of immuno-suppressants with which Crohns are so familiar.  Repair is seldom highlighted as it should be -- excepting methods of balancing gut flora.

The team of scientists in France, lead by one Frederic Andre, looked at the beneficial effects of Sb in both mice and an in vitro wound model (this is a strain of cultured epithelial cells which are attacked gently with a toothpick... rather cute).

The first major finding was that mice who were fed Sb for one week doubled new epithelial cell migration.  Only one downer for me in this study was that the mice were all healthy, with no in vivo IBD model for comparison.  Nonetheless quite encouraging, no?

The second conclusion was that the wounded cell line closed its wound (or, repaired its injury) by roughly 70%.  Their video supplement to this end is quite something.

The scientists conclude that Sb improves new epithelial migration both in vivo and in vitro.  Interestingly, the study suggests that increased migration is due to increased motility of cells and not to increased proliferation (the generation of new cells).  Sb may be stimulating this activity by secreting factors that stimulate  a target signaling pathway FAX/paxillin, which leads to several physiological changes in the intestinal epithelial lining that enable motility of new epithelial cells.

The thing about supplement studies such as this one is that they make me want to stop by the grocery and pick some up on my way home...


Canonici A, Siret C, Pellegrino E, Pontier-Bres R, Pouyet L, Montero MP, Colin C, Czerucka D, Rigot V, & André F (2011). Saccharomyces boulardii Improves Intestinal Cell Restitution through Activation of the α2β1 Integrin Collagen Receptor. PloS one, 6 (3) PMID: 21483797

SfN 2010: Tuesday

Tuesday was the biggest day of the conference, for me.  While I maintained my initial pace during poster sessions, I soon discovered that on days when those posters were scattered throughout the convention hall, my body was substantially more taxed by the end of the day.  Tuesday was no exception, as the morning encompassed introducing myself via poster speculation to three potential mentors, each in a different subtopic of the session.

I succeeded in making a fool of myself in introduction to one such PI, by attempting to hide behind other poster surveyors until I was equipped with intelligent questions about his research.  My scheme unraveled when he recognized the name on my badge and made the introduction himself.  I spun a subterfuge of embarrassed chatter until recovering my intellect.  Fortunately, he stopped by my poster in the afternoon and was enthusiastic and impressed.  Score.

A dear late post doc of our neighboring lab, now working in industry as a medical liaison, imparted some wisdom regarding the giant that is SfN.  "What is unique about this conference," she said, "is that what your experience here changes each year as your career changes."  When you are a graduate student, your mission is to soak up any and all information about other research that may help design your own.  When you are a post doc, you are sponging in addition to networking.  When you are a PI, you are peppering your collaborative learning with reunions and lunch dates.  In industry, she says, you are honing in on studies where drug intervention studies may be beneficial for your company, as well as attending committee meetings.  SfN is consistently a whole 'nother world  defined by where you are outside of it.

And, I suppose, as a pre-pre-doc, my mission this year was to get my feet wet, to network, to get some face time with potential mentors and, of course, benefit from poster feedback on my own research.  In all of these regards, I believe I was successful.

Tuesday afternoon was my poster session, and though I initially planned on holding the fort for two of the four hours, both my boss and myself were present for almost the entire session breaking away for no more than half an hour each to visit other posters.  Thank goodness for my wonderful colleague who fielded questions in our brief absences even though she works with a different model!  By half an hour into the session, the traffic in front of our poster was boggling.  My boss and I ended up tag-teaming presentation/question rounds for different handfuls of people. The feedback was spectacular, with several unique directions offered, several potential collaborations resulting and a few friends made.

What's more, I was totally starstruck by the flow of big names in front of our poster whose badges I recognized from manuscripts that had jump-started my career or helped to define my work, but whose faces were met for the first time.  At one point I remember surreptitiously asking my boss, "is that the Mike Salvatore?"  What a rush to present and discuss your work with minds whose contributions to neuroscience have shaped your own, and what an even greater honor to be commended by them for your ideas.  These folks are all friends of my boss -- you come to know or at least meet most of your field at some point -- and he got a kick out of my agog state.

SfN 2010: Monday

Monday morning's highlight was the Experience-Dependent Synaptic Plasticity and Neurogenesis in the Degenerating and Injured Brain nanosymposia session.


Carl Cotman, professor of neurology at UC Irvine and a potential mentor, spoke about the effects of exercise in mice, canines and humans.  Dr. Cotman specializes in Alzheimer's (AD) research, and presented a collection of studies highlighting the effect of exercise on blood flow, amyloid aggregation and instance of BDNF.  In transgenic mouse models of AD (Tg2576), Cotman discussed reduced amyloid and increased BDNF with exercise.  In humans with AD, increased vessel volume and blood flow was observed with fast walking, corroborative with decreased amyloid reported by Liang et al in the Annals of Neurology this year.


Most notably, Dr. Cotman proposed that the brain "has a memory for exercise."  Exemplifying this statement was his study from 2005 where AD rats exercised on a treadmill for one week, resulting in increased BDNF in the hippocampus.  Some of these rats proceeded without exercise in the following week which resulted in decreased BDNF levels.   These levels increased rapidly when the animals were exercised for an additional week to levels beyond those revealed due to the initial exposure, a phenomenon that typically takes weeks to induce in naive rats.  This "memory for exercise" may prove to be key in designing rehabilitative exercise programs.


Mike Jakowec and Giselle Petzinger, respectively professor and clinician-researcher at USC, represented the recent work of their labs as well as the strong collaborative efforts within USC's Neuroscience labs.  Advocate of exercise in rodent models of Parkinson's disease, Dr. Petzinger presented evidence that exercise may be working through the indirect dopamine pathway (D2) to aide motor recovery.  Mot strikingly to me, their lab has reported that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) results in dopamine neuron spine loss specific to the D2 pathway via [F]Fallypride radiotracing (PET scan).  Exercise in their MPTP mouse model results in a 98% increase in the striatal D2 receptor.  This research suggests some very interesting targets for intervention.


The David Kopf lecture on Neuroethics was given this year by Hank Greely, professor of law at Stanford, and a professor by courtesy of genetics at the School of Medicine.  Beyond delivering a lecture as eloquently as one will ever hear, the poignant stars of Dr. Greely's talk were copious.


Dr. Greely opened by saying that the "ethical issues of neuroscience are 10 years behind those in genetics," referring to the paradigm sweeps that genetic discoveries have prompted (i.e. eugenics).  He elaborated that the implications of neuroscientific discovery were "more important than [those of] genetics, made so by immediacy and power."  Namely, neurological dysfunction has very present consequences, whereas genetic abnormalities must emerge on the physiological level before they can be acted upon.  For instance, if you were to find yourself predisposed to Alzheimer's through genetic testing, you would be protected from discrimination by the Genetic Information Non-discrimination Act of 2008.  However, there exists no such protection if you are diagnosed via MRI.


Humans as mind-readers, MRI's distinguishing between conscious and unconscious vegetative states, and the responsibility of humanity to discern what is an adverse disease and what is just a condition that makes "us" (the indirectly affected "us") uncomfortable:  these are some of many issues with which neuroscientists can become dangerously dissociated, but the bench does not separate us from the issues produced by our discoveries.  The mindfulness of scientists guides social consequences.


I refer readers to Stanford's Neuroblog and The Neuro Dilettante for more adequate coverage of Greely's lecture.



Liang KY, Mintun MA, Fagan AM, Goate AM, Bugg JM, Holtzman DM, Morris JC, & Head D (2010). Exercise and Alzheimer's disease biomarkers in cognitively normal older adults. Annals of neurology, 68 (3), 311-8 PMID: 20818789


Adlard, P. (2005). Voluntary Exercise Decreases Amyloid Load in a Transgenic Model of Alzheimer's Disease Journal of Neuroscience, 25 (17), 4217-4221 DOI: 10.1523/JNEUROSCI.0496-05.2005

SfN 2010: Sunday

Before I extrapolate on neuroscientific happenings, I must take this opportunity to reflect on how stellar it is that I am staying on a docked yacht, and drinking margaritas at sunset on the deck of said yacht with two extraordinary people.

Onward.

Sunday was booked with two four-hour poster sessions and one afternoon symposium.  The morning was filled with Spinal Cord Injury and Parkinson's Therapies sessions, with a not-so-quick diversion to the triple-letter aisles where one of my prospective graduate program PIs sported sixteen -- count 'em, sixteen -- posters on expression of the immediate early gene Arc in various brain regions associated with cognition in models of aging and environmental stimulation (Session 204. Learning and Memory: Genes and Aging).

The afternoon's symposium of choice was Silvia Arber's talk on Motor Circuits, which was excellent but for a somewhat misleading in title.  This particular neuroscientist sees "Connecting Motor Circuits" and expects a comprehensive discussion of relationships of both central and peripheral nervous system motor circuits.  Instead, Dr. Arber focused on her research, which is entirely peripheral and has become famous for classifying the proprioceptive identity of the spinal cord; specifically, the innervation of the dorsal and ventral horns, and during what movements their respective peripheral pathways are activated.  Numerous beautifully conducted studies were exemplified during her talk.

An afternoon of inducing, protecting against and ameliorating dyskinesias brought me back to my element, but my brain was re-tuned once more with a quick tour through the vendor exhibits.  The vendors first open shop on Sunday, and traffic through their booths was daunting.  Free widgets, pens and t-shirts galore spanned the entire length of the convention center; I am told that there were significantly more vendors this year than ever before.

Adorned with newly acquired tote bags full of free scincey goodies, off we went to the The Fish Market on Harbor Drive to pick up some prawns to accompany our margaritas -- peeled, cooked and devoured on our boat.

SfN 2010: Saturday

Glenn Close has been a heroine of mine since 1991, when I saw her in Sarah Plain and Tall.  Today, I met her... almost.

Glenn Close, her sister Jessie Close and nephew Calen Pick were the introduction to my first SfN.  Their stories of battling bipolar disorder and schizoaffective disorder were strong, and deeply touching.  Bringchange2mind.org has done a fantastic job of reaching out to people with or touched by mental illness; and communicating to the world that mental illness is a physical ailment like any other of the body, not to be isolated as demonic or self-inflicted.  Calen spoke of the self-hatred coincident with not being able to control your own stream of consciousness or emotion, and the effort that bringchange2mind puts toward erasing this attitude from Consumers, survivors and loved ones whose lives are impacted.  One in four families is touched by mental illness, Glenn reminded us.

Jessie and Calen gave very personal insight into their struggles to find and hold on to reality, and opened a week-long convention of cutting edge research by suggesting that neuroscientists like those present were responsible for their current states of health.  It is so infrequently in science that people look at your work and say, "this is so beautiful, what you've done."  And it was profoundly impactful to me to hear Calen Pick thank the present body of researchers for their work.  From an artist, that is an especially beautiful complement.

The afternoon's first poster session was overwhelming only in that I did not expect to be pumping so much adrenaline.  Twenty-six posters interrupted by a nanosymposium was a good pace.  However, my session frequency was all over the place, and I spanned the length of the convention center from the single to the triple letter aisles more than once.  The following days were much more focused.

Nearing 5pm, as I walked out of the center I passed Glenn and Jessie Close and Calen Pick in the company of their entourage.  In the ten seconds during which I approached and then passed them by, I made eye contact, smiled and nodded respectfully, chickened out of approaching and asking to shake the hand of my emotive activist childhood heroine, and regretted it.  Thus began the epicness of my first SfN. 

Society for Neuroscience, 2010: An Introduction

The next several posts will be SfN-centric, as it is my first year of both attending and presenting and I am teeming with fledgling excitement.  So that I am not undone by the insidious and unrealistic lure to see and do everything, I have been following the guidance of a few Neurobloggers and of my boss.

After going through the almost innumerable legions of posters and symposia in the Meeting Planner by session, then doing separate name and keyword searches, I realized that getting the most out of every one of the many hundreds of titles I had ear marked was just not realistic.  Though I have not slimmed down my itinerary, I have taken the sage advice of The Neuro Dilettante, and acknowledged that even if I visit all the posters on my itinerary, I will have only seen a minute fraction of what this mass international gathering has to offer, and that is fine.

I am told that many first-timers (mostly grad students) burn out within the first two days attempting to see and learn about everything.  In the interest of surviving the entire week, I will not be rushing about with my laptop or busily scratching volumes of notes.  Instead, the most key research conclusions or methodology along with contact information will be incorporated into my notepad.  And if I happen to spend a little extra time at the posters presented by the PI's with whom I'm interested in doing my PhD work (in two years, universe willing)... so be it.

And I intend to exploit the free give-aways of the vendors who have taken the time to email me with specific requests for demonstration and face time.  Can one have too many key chain laser pointers or letter openers? 

I will also be equipped with thumb tacks, mini-poster hand-outs, sharpies, bottled water, a sweater (yes, though San Diego will be between 70-80 degrees the convention center is kept at a chill), and convention center floor plans.

Following the high of seeing Glen Close, heroine of my childhood, on Saturday afternoon, the Navigating the Meeting seminar may be just the thing to settle me into conference mode -- I highly recommend this tool, especially for those who do not yet have plans of attack.  I intend to be a SfN Ninja by the end of this.

Journal Club Follow-Up: Coenzyme Q10

Many Parkinson's patients take Coenzyme Q10 supplements.  As mentioned in the previous post, CoQ10 is part of the Electron Transport Chain -- a very important part, in fact, as it alleviates pressure on our precarious and susceptible-to-aging Complex I.

While many theorize that Complex I is shut down or is deficient in PD (1, 2, 3, 4), others believe that deficient activity of the CoQ10 pool beside Complex I is more to blame (5, 6).  The CoQ10 theory claims that PD causes a deficiency in the CoQ10 pool that carries electrons from Complex I to their next destination without producing ROS.  As a result of low CoQ10, electrons build up in Complex I and get released from the entrance because they cannot leave through the exit.

Some PD patients are able to take CoQ10 supplements and improve their condition (7).

It is my opinion that CoQ10 is a palliative treatment and not a long-term solution.  The Ndi1gene therapy discussed in the previous post is a better option if it makes it to, and proves robust in clinical trials.  My reasoning is that a genetic replacement for Complex I is a more stable therapy than a persistent aid to CoQ10: it is more permanent and a more widespread solution; a large portion of PD patients do not have CoQ10 deficiencies.  Ndi1 would also contribute to the sustaining of the proton gradient in the mitochondria, also vital to creating energy in the ETC.


Greenamyre, J. (2001). Response: Parkinson's disease, pesticides and mitochondrial dysfunction Trends in Neurosciences, 24 (5) DOI: 10.1016/S0166-2236(00)01788-4

Schapira AH (1994). Evidence for mitochondrial dysfunction in Parkinson's disease--a critical appraisal. Movement disorders : official journal of the Movement Disorder Society, 9 (2), 125-38 PMID: 8196673

Morais, V., Verstreken, P., Roethig, A., Smet, J., Snellinx, A., Vanbrabant, M., Haddad, D., Frezza, C., Mandemakers, W., Vogt-Weisenhorn, D., Van Coster, R., Wurst, W., Scorrano, L., & De Strooper, B. (2009). Parkinson's disease mutations in PINK1 result in decreased Complex I activity and deficient synaptic function EMBO Molecular Medicine, 1 (2), 99-111 DOI: 10.1002/emmm.200900006

Storch, A., Jost, W., Vieregge, P., Spiegel, J., Greulich, W., Durner, J., Muller, T., Kupsch, A., Henningsen, H., Oertel, W., Fuchs, G., Kuhn, W., Niklowitz, P., Koch, R., Herting, B., Reichmann, H., & , . (2007). Randomized, Double-blind, Placebo-Controlled Trial on Symptomatic Effects of Coenzyme Q10 in Parkinson Disease Archives of Neurology, 64 (7), 938-944 DOI: 10.1001/archneur.64.7.nct60005

Journal Club: Neuroprotection by NGI1 Gene in a Parkinson's Disease Model

One of the most popular mechanisms of pathology in Parkinson's disease (PD) research is cell death through Complex I inhibition in the mitochondria.

Mitochondria -- affectionately known as the power houses of all cells -- are where energy is produced.  There is a series of protein complexes forming the Electron Transport Chain (ETC) which, as their acronym exposes, steal electrons from contributing molecules and convert them into energy and water.

The fully reduced H2O form of oxygen is non-toxic.  The various single-electron intermediates between O2 and H2O are ALL toxic free radicals, the so-called Reactive Oxygen Species (ROS).  Complex IV (cytochrome oxidase complex) has a gate that transfers electrons directly to O2, reducing it to water without generating ROS.  Complexes I and III, however, occasionally allow electrons to escape from the ETC to form ROS.

In Parkinson's disease, Complex I is dysfunctional, and it is thought that much higher concentrations of ROS are produced in the ETC.  These attack multiple systems in the mitochondria which eventually lead to the breakdown of cellular DNA, and the cell itself.

Many cases of PD are characterized post mortem by a selective loss of dopamine cells via this mechanism.

The study by Marella et al has used the variant of Complex 1 found in yeast to attempt to quell this rampant ROS formation.  Using the rotenone rat model, the group injected the Ndi1 gene via biodegradable microspheres (classy...), and monitored recovery in the substantia nigra pars compacta (SNpc; the primary region of dopamine cell loss) and in behavior.

After 60 days, tissue analysis of Ndi1-injected rotenone rats showed increased staining for viable dopamine cells in the SNpc.  Those lesioned rats who did not receive the Ndi1 gene showed significantly fewer stained dopamine cells, and extensive staining with antibody against 8-oxo-dG (indicating oxidative damage to DNA).

My gripe with the study -- in addition to its not being tremendously written -- is that it is lacking in relevant behavioral assessment.  The study monitored speed of movement, and the number of rotations in a widely used apomorphine test.  The rotations test is normally used in unilaterally lesioned animals (which these were) to indicate preference to rotate in one direction.  However, the direction of rotation induced by apomorphine in this study was determined by more factors than the unilateral lesion, which caused the animals to rotate in both directions.  Therefore, behavioral data was reported as the "number of animals exhibiting 100% lateralized rotation irrespective of the direction."  In my opinion, the behavioral test was severely weakened by this caveat and the group should have employed a quick additional test... like the Whisker test or lateralized grip strength.

This suggests that the Ndi1 gene -- the yeast version of Complex 1 -- was able to compensate for inhibition of Complex 1 by rotenone, decrease ROS activity by serving as an electron transporter, and lessen cell death.  If this could be replicated in higher animals, it may prove a viable candidate for clinical trials. 

Aside from deficits in writing and behavioral analysis, the story told by this article was fascinating with  very intriguing implications.   They did their homework, publishing several studies on in vitro activity of the Ndi1 gene and subsequent protein (1, 2) as well as confirming benign effects of introducing a yeast gene in vivo (1, 2)  .

Marella M, Seo BB, Nakamaru-Ogiso E, Greenamyre JT, Matsuno-Yagi A, & Yagi T (2008). Protection by the NDI1 gene against neurodegeneration in a rotenone rat model of Parkinson's disease. PloS one, 3 (1) PMID: 18197244

gene patenting

This week's Science Friday focused on gene patenting.  Specifically, a case that has been in court since May of 2009: the American Civil Liberties Union (ACLU) -- along with several cancer patients and organizations of pathologists -- has raised a lawsuit against Myriad Genetics' patenting of the two genes BRCA1 and BRCA2.  Mutations of these genes are indicative of increased risk of breast and ovarian cancer.

The ACLU claims that Myriad's 1994 patent on the genes is illegal, unconstitutional and should be thrown out.  The issue of importance to the cancer patients involved is that Myriad's monopoly on the tests for mutated BRCA1 and 2 prevents patients from getting a second opinion on the results of their tests, and from obtaining a more affordable version of the test.

In my mind, patenting genes is like patenting anything else in medicine.  By invoking a 20-year period of exclusive rights, development of the patented technology or drug is inhibited.  This is the way it has worked with pharmaceuticals for eons: drugs remain produced, distributed and exorbitantly priced by the pharmaceutical companies who patent them, and become eligible for other companies to optimize and distribute generically when that 20-year period is up.

The opposition to this argument is that patenting genes causes more stunting to medical innovation -- and, by default, medical cures -- than does patenting of drugs and other medical technology.  By patenting genes and the single test that has been developed to identify them, patients interested in the risk those genes may pose to them are forced to rely on the interpretation of the patenting company.  In the case of BRCA1 and 2, patients cannot get a second opinion outside of Myriad Genetics; they are forced to rely on the results obtained from Myriad's test and on the interpretation of Myriad's doctors.

My response to this opposition is as follows:

Genes are only a single indication of disease.  It has been reported that  "inherited BRCA1 and BRCA2 mutations account for 5 to 10 percent of breast cancers and 10 to 15 percent of ovarian cancers among white women in the United States" (Campeau et al 2008) -- having the mutations is not a definitive diagnosis of cancer.  It has also been reported that this percentage is even smaller: "[a]pproximately 5-10% of breast carcinomas and 10% of ovarian carcinomas are ascribable to a genetic susceptibility. Of these, about 40% are related to genetic mutations in the genes BRCA1 and BRCA2" (Palma et al 2006).  Take from that statistical discrepancy what you will -- I guarantee there was not a new census taken between 2006 and 2008.

If patenting of genes inhibits patients from getting a second opinion on their genetic tests, it seems that seeking a verification through other diagnostic methods is not only an acceptable option, but a preferable one.  Treatment of breast/ovarian cancers in particular are radically invasive and life-altering; until the BRCA gene identification tests are available "generically", mammograms,  MRI and screenings for other genetic markers of breast/ovarian cancers are not only options but -- in my very humble opinion -- an incredibly good idea before making decisions about radical mastectomy and chemo:

"Clinical testing options for BRCA1 and BRCA2 are limited in the United States. In contrast to genetic testing for BRCA1 and BRCA2, genetic testing for other cancer susceptibility genes (MSH2, MLH1, PTEN, TP53, etc) is available from numerous profit and notfor- profit laboratories, with a range of testing options and prices."

"In addition to DNA sequencing of BRCA1 and BRCA2, genetic testing for other major breast cancer susceptibility genes including CHEK2, PTEN, and TP53 is clinically available in the United States." (Walsh et al 2008)

 Patients at risk for cancer should not limit their diagnosis to the outcome of a single kind of test when there are several out there, and certainly not to a single genetic test which measures only susceptibility.  I do not argue against the legitimacy of a patient's concern, I just don't think that this particular argument is reasonable ground to make illegal the patenting of genes by their discoverers.

I am not sure I agree with the ACLU's argument either:

“What they have really patented,” says Chris Hansen of the ACLU to the New York Times, “is knowledge.” 

Really?  If that is a legitimate statement, then every biomedical patent in the world is a blockade against knowledge, and they should all be overturned.  Patenting is a measure taken to protect and honor the discoveries of researchers.  It gives them the opportunity to make advancements on their own discoveries before the whole world is allowed to take a crack at them.

"Genes are informational. [By] allowing a company to have a patent on the actual sequence you are restricting the free flow of information," Tania Simoncelli, ACLU's science advisor, told Pharmacogenomics Reporter back in May.  Simoncelli's colorful expatiation of this comment can be found here.

THE POINT OF PATENTS IS TO TEMPORARILY RESTRICT THE FLOW OF INFORMATION.  IF YOU WANT TO BRING THE FIRST AMENDMENT INTO THIS, YOU HAVE TO FIGHT ALL PATENTING OF ALL DISCOVERIES EVER.

BIOMEDICAL RESEARCH HAS BEEN PATENTING GENES SINCE THE 1980's AND DOCTORS HAVE BEEN PISSED OFF ABOUT IT SINCE THE 1980's.  IF THE PATENT OFFICE WAS WORRIED ABOUT GENE PATENTING BEING CONTRARY TO THE PUBLIC INTEREST, THEY WOULD NOT ISSUE THEM.

In short, I have yet to find a legitimate argument made by the ACLU against patenting the BRCA1 and 2 genes, much less any gene.  I'm not saying that genes should or should not be patentable; what I'm saying is that the ACLU is making a poor argument, and needs to approach this from more of a patient access angle.

Maybe what needs to happen here is for gene patenting to selectively be restricted to 5 years instead of 20.  Five years is nothing from a scientific standpoint, and wouldn't actually allow researchers the opportunity to make significant headway before the rest of the world chimed in, but it would at least give them a head start without making prospective patients wait an inordinate amount of time for reasonable diagnosis or treatment.  And five years of profit from over-priced tests certainly ain't bad.

in vitro meat and the de-evolution of homo sapiens

Homo sapiens is Latin for wise or knowing man.  I would like to strike "sapiens" from our evolutionary title and replace it with "homo follis", which is Latin for windbag or foolish man.  Can I do that?

Normally, I love technology and am all for its advancement as long as there is an antidote should it prove to be physically or ethically harmful.  There is a line, however, over which technological advancement frequently crosses into the world of promulgating sheer gluttonous sloth.  The antedote in the case of modern animal farming is to change human behavior.  If we consume less meat, farmers aren't pressured to over-produce massive qunatities in order to stay economically competitive.  Less pressure to over-produce means less incentive to abuse farmed animals with antibiotics, hormones, extremely unhealthy food and other revolting living conditions.

But is the American populous ready to make that sacrifice for the sake of being humane?  You bet your ass we're not.  Instead, commercial science has discovered a much more attractive antidote to modern animal farming -- one that requires significantly less effort on the part of the consumer than reducing meat consumption.  For the last decade or so, scientists have been learning how to culture "meat" in a petri dish (Datar & Betti 2009; Edelman et al 2005).  We (the people) are so lazy and so addicted to meat that scientists and economists have fleshed out an analysis of the viability of in vitro meat culturing as a "replacement" for meat farming (In Vitro Meat Consortium 2008).

Is it less of a personal burden to adjust to the taste of stem cell meat than to eat less meat and/or eat more local/grassfed/humanely farmed meat?  The In Vitro Meat Consortium seems to think so, as does PETA:

"As far as we’re concerned, if meat is no longer a piece of a dead animal there’s no ethical objection." 

Really?  Because I'm pretty sure that teaching humanity survival through relying on technology to save us from having to make proactive changes in our behavior has negative ethical implications.  For instance, the backward evolution of our species. 

"Lab-grown meat isn't an easy sell, but there could be benefits. Designer meat would theoretically be free of hormones, antibiotics, and the threat of mad cow disease or bird flu. Omega-3 fatty acids and vitamins could be blasted into the mixture ", says Ian Christe in his article in Popular Mechanics on the subject.

Yes, Ian, you are absolutely correct.  However, HUMANELY FARMED ANIMALS WOULD ALSO BE THEORETICALLY FREE OF HORMONES, ANTIBIOTICS AND THE THREAT OF MAD COW DISEASE OR BIRD FLU.  Additionally, OMEGA-3 FATTY ACIDS AND VITAMINS ARE PRESENT IN FREE-ROAMING UNGULATES WHO ARE NOT PUMPED FULL OF GRAIN-BASED SLOP TO FATTEN THEM UP ALL YEAR ROUND.  And further, WHAT ABOUT ALL THE OTHER SUBSTANCES THAT ARE USED IN THE CULTURING OF THE MEAT; MUST WE ASSUME (like idiots) THEY WILL BE TOTALLY HARMLESS?

So, I must pose the final question: will humanity prefer the financial burden of commercial in vitro meat production, or the burden of changing their consumptive behavior in order to promote humane animal farming?  Unfortunately, I fear the former may win out. 

Lastly, a warm thank you to PETA for supporting the de-evolution of humanity (not that I'm surprised), as well as an alternative to industrially farmed meat that wont actually stop anyone who wants to taste real meat from doing so (tofu dogs have already made this attempt).

phthalates and ADHD

The outstanding debate on whether the benefits of soft plastics outweigh their potential harms continues. 

The group of esters called phthalates are used in an array of products ranging from pill capsules to children's toys to shower curtains.  A research group in Korea has found a strong positive correlation between ADHD behavioral characteristics and phthalate metabolites in the urine of Korean school children.  This is a particularly important study for two reasons: 1) a correlation between ADHD and phthalate exposure during critical periods of development has never been shown, and 2) the metabolite levels found in these children indicates the amount of exposure that can now be replicated in animal models.

"Previous animal studies (6,15,16) have shown that phthalate related metabolites induce hyperactivity in rats. These studies reported that pups treated with phthalate demonstrated 1.4 times the level of hyperactivity at night compared with control subjects. Such hyperactivity was dose-dependent, which is consistent with the results of our study."

"It is possible that the toxicity of phthalates is attributable to degeneration of dopaminergic neurons, leading to the hyperkinetics observed in rats in cases of 6-hydroxydopamine (OHDA) procedures (27). Well-known animal models of ADHD like the OHDA rat model suggest that the dopamine neuronal damage can provoke hyperactivity and impulsivity. Many structural magnetic resonance imaging studies showed striatal volume loss suggesting the dopamine neuronal loss in ADHD patients (28)."

"With DNA macroarray data, researchers have found that phthalate metabolites change
the expression patterns of various genes, including both the dopamine receptor D4 (DRD4) and the dopamine transporter in the midbrain (6). The dopamine receptor D4 and dopamine transporter gene expression modulation can induce changes in extracellular dopamine and neuronal dopamine sensitivity, resulting in hyperactivity and impulsivity in rats."

Here is something particularly interesting: if excessive exposure to phthalates is linked causally to ADHD phenotypes -- which has yet to be explored -- perhaps the time-release medications used to treat ADHD such as Wellbutrin and Ritalin should cease to use phthalates in the enteric coating of their medications.  It seems odd that they are so widely used in films of pharmaceutical capsules if for no other reason than their heavy reputation as endocrine disruptors.  Capsules can contain in the range of 3600 ug phthalates, while most studies estimate that the "safe" exposure range is near 20 ug per kilogram body weight.  That means the "safe" range for most young children is about 750 ug.  Note that phthalates do not bioaccumulate, so exposure levels are dailies.

"The bupropion (Wellbutrin® SR)  release rate has been improved by the introduction of two types of film coated active pellets that release the drug at different pH resulting in novel dissolution profiles. Inert spheres are initially coated with bupropion and hydroxypropyl methylcellulose. The active pellets containing bupropion comprise 70-75 weight % of the dosage form. An enteric coating, applied to about one third of the active drug pellets, is comprised of a film insoluble at low pH, such as hydroxypropyl methylcellulose phthalate. The second coating applied to the other two thirds of active drug pellets is comprised of a combination of a hydrophobic coating agent and methyl acrylic acid copolymer. The two pellet types are then combined in a capsule."

"The novel dosage forms are used to administer methylphenidate (Ritalin) in a pulsatile release manner... Suitable membrane coating materials for effecting delayed release include, but are not limited to: cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropylmethyl cellulose phthalate, cellulose ester-ether phthalate, hydroxypropylcellulose phthalate, alkali salts of cellulose acetate phthalate, alkaline earth salts of cellulose acetate phthalate, hydroxypropylmethyl cellulose hexahydrophthalate, cellulose acetate hexahydrophthalate..."

Journal Club: on the selective degeneration of dopamine neurons in Parkinson's disease

http://www.ncbi.nlm.nih.gov/pubmed/16299504

The therapeutic application of potassium gated ATP channels (K-ATP) in Parkinson's disease arises from their ubiquitous expression in the basal ganglia.  Regulation of these channels evokes cell hyperpolarization in order to prevent cell excitability.  In the mitrochondria, they play a role in translating the metabolic state of the neuron.  This week's journal club discussed an article suggesting that K-ATP channels are necessary for the selective vulnerability of dopamine neurons in the substantia nigra pars compacta (SNpc) relative to the ventral tegmental area (VTA).   Liss et al demonstrate this theory using mitrochondrial complex I inhibitors rotenone and MPP+, both neurotoxins commonly used in developing Parkinson's disease models in rodents.

Rotenone and MPP+ are known to selectively degenerate dopamine neurons of the SNpc, leaving the VTA dopamine neurons primarily in tact.  Liss et al suggest that this phenomenon is due to differential mitochondrial uncoupling (or, disruption of metabolism).  Extensive uncoupling with the application of FCCP resulted in activation of K-ATP channels in both the SNpc and VTA.  Mild uncoupling with FCCP did not activate K-ATP channels in either region.

"Notably, however, mild uncoupling inverted the response of K-ATP channels to complex I inhibition: in this case, VTA DA neurons, but not SN DA neurons, were hyperpolarized and functionally silenced due to K-ATP channel activation. In the presence of 50 nM FCCP, none of the SN DA neurons was significantly affected by 100 nM rotenone (Fig. 5a,b, left; perforatedpatch recording in 50 nM FCCP: 2.33 ± 0.29 Hz; FCCP + rotenone: 1.92 ± 0.36, n ¼ 6; P ¼ 0.40) or 10 mM MPP+ (data not shown). In contrast, the presence of 50 nM FCCP sensitized K-ATP channels of VTA DA neurons to complex I inhibition (Fig. 5a,b, right; 50 nM FCCP: 2.4 ± 0.55 Hz; FCCP + rotenone: 0 ± 0 Hz, n ¼ 6; P ¼ 0.0075)."

"Stereological analysis of all SN pars compacta neurons in hematoxylin-eosin counterstained sections demonstrated genuineMPTP-induced neuronal death in wildtype mice and confirmed the complete rescue of SN neurons in the Kir6.2-/- mice (Fig. 6d, middle panel; Kir6.2+/+ SN: control, 11,882 ± 222; post MPTP, 8,061 ± 632, P ¼ 0.029; Kir6.2 -/- SN: control, 12,288 ± 231; post-MPTP, 12,619 ± 223; P ¼ 0.36; n ¼ 3 each)." ** Kir6.2 -/- mice are a genetic strain not expressing a unit of the K-ATP channel necessary for activation.  This means that blocking the channel's activity prevented SN DA neurons from being lost.

I want to see some apoptosis markers in these SNpc DA neurons due to K-ATP activity.  The comaprison of SNpc and VTA DA neurons is an invaluable resource for identifying mechanisms of the selective degeneration that marks Parkinson's disease.  Because the VTA DA neuron population is so identifiably unaffected by most neurotoxins from which Parkinson's models are developed, the selectivity of the models and the degree of neural degeneration is not only measurable but comparable to many cellular mechanisms of the disease itself.  Uncoupling of the mitochondria speaks to selective metabolic toxicity, and a new target for neuroprotective therapies.

** This was a very complex article using six different mouse strains/treatment groups and analyzing the cell viability using electrophysiology, histology and RT-PCR -- I am reciting only the briefest summary which does not to justice to the extensive work done (although my critique is long-winded, I was impressed with these studies).

autism spectrum disorders, part deux

Another instance where the question begs to be asked: are handwriting patterns differentiated between autistic and Asperger children?

This study found quality of letter formation in the handwriting of children with ASD to be lower than in normally developing children.  The subject hasn't really been addressed since 2001, when Beversdorf et al identified the significant instance of macrographia in patients with ASD, as compared to age- and IQ-matched control subjects.  Both studies have subsumed autism and Asperger into the ASD umbrella -- just as likely for the purposes of procuring a larger test subject sample as for making their results widely applicable:

"Whereas all subjects with autism spectrum disorder met the diagnostic criteria for autism through their reported behavior during childhood, most subjects had demonstrated significant improvement in function over time, such that the distinction between the various forms of autism spectrum disorder was not as clear. Therefore the more general term autism spectrum disorder is used to describe these patients." (Beversdorf)

The original description of Asperger syndrome in 1944 noted difficulties in motor coordination, specifically in handwriting (Frith; translated 1991).  One year before, Leo Kanner published his first paper asserting that some autistic children were quite agile, performing "hair-raising feats of balancing," while others were clumsy "despite dextrous manipulation of objects" (Frith pg. 95). 

I would love to see a study comparing the different aspects of handwriting using both the Revised Physical and Neurological Examination for Subtle Sign (from the Kennedy Krieger Institute study), and the Autism Spectrum Quotient and Empathy Quotient tests used by Baron-Cohen's group to differentiate autism and Asperger syndrome.  Any cerebellar distinctions between autism and Asperger could be very illuminating...

autism spectrum disorders and dsm-v politics

An article in the New York Times this morning by Simon Baron-Cohen addressed the debate in the DSM committee over subsuming the conditions of Autism and Aspergers in the fifth edition of the "psychiatric bible"(promised in 2012).  The committee is deliberating whether or not to eliminate Asperger from the diagnostic manual and characterize its discrete symptoms as a degree of autism in the spectrum (perhaps "intermediate functioning autism").

Autism and Asperger syndrome are both characterized by impaired communication skills, a desire for keenly focused stimuli and strong inclination toward repetition. They are distinguished only by a slower onset of language skills and latency of intelligence in autism, says Baron-Cohen.  He further suggests that this distinction is proving not to be concrete enough, and that the DSM-V committee's struggle with the controversy can be attributed to the lack of physiological distinction of these psychiatric conditions.

I would agree with Baron-Cohen that there is not currently enough genetic distinction between autism and Asperger syndrome to warrant their being entirely separate conditions outside the spectrum disorders umbrella in the DSM-V.  However, I think that defining Asperger syndrome idiosyncratically is important to preserve in the new manual.  Here is why:   

1)  Baron-Cohen mentions his own group's recent identification of 14 Asperger-specific genes,19 genes specific to autism and 7 shared (Chakrabarti et al 2009).  They measured 68 candidate genes in two experiments: the first measured autistic traits in an undiagnosed sample population using the Autism Spectrum Quotient; the second, using the Empathy Quotient.  These two experiments were designed to identify autistic and Asperger cases among the sample:

"We searched for common genetic variants (single nucleotide polymorphisms (SNPs)) on the assumption that autistic traits are continuously distributed in the general population [Constantino & Todd, 2005; Sung et al., 2005]."

"In Experiment 1, autistic traits (measured on AQ and/or EQ) were nominally associated at P<0.05 with SNPs from 19 genes. In Experiment 2, SNPs from 14 genes were nominally associated at P<0.05 with AS."

Six genes were nominally significant in both experiments. This study alone suggests that Asperger syndrome deserves a distinction as a sub-group in the Autism Spectrum Disorders (ASD) category that the DSM-V committee is considering, as opposed to eliminating it entirely, as is also being considered.

The Charkrabarti study is impressive, and the first step in the important attempt to identify the genetic and epigenetic correlates of autism and Asperger separately.  However, there is still an extensive amount of correlative research to be done.  A good amount of this is ongoing through the AutDB Project.

2)  If for no other reason than to preserve the honor of the venerable Hans Asperger.

3)  To keep company the solitary other recognized ASD, Pervasive Developmental Disorder - Not Otherwise Specified (PDD-NOS).*  Perhaps these could both become sub-groups in the ASD category.

It is noteworthy that a great deal of genetic research already refer to their studies as ASD interactions/links/correlations (PubMed or Google Scholar this).  I am terribly eager to find out whether or not this plays a strong role in the decision of the DSM-V committee.


*High- and Low-functioning autism are not classified as spectrum disorder subgroups, although they should be... and perhaps, one day, will be, provided there is a physiological distinction to be drawn between them, Asperger and PDD-NOS.

empty thoughts X

I perceive evolution of knowledge not as continually growing and expanding, but as serially destroyed and recreated.

Expansion is a popular chimera of growth. We think of the universe in terms of ever-orbiting away from those centers that we have identified. We think of political change as manifestation of new direction. We think of steps forward in technology as bursting revelations. But are all of these things not brought about by reconfiguring previous conceptions?

Matter is never either created or destroyed, but recycled. On a quantum level, that's almost always true. On a grossly observable level - the level of content - it is created and destroyed all the time. Not a thing has been brought to my attention that would suggest the growth of knowledge proceeding any differently.

why neuroscience?

In preparation for meeting with the future of my academic career next week, I set about answering some silly interview questions. The first of these was, naturally, "why do you want to do research in neuroscience?" So I thought I'd share it, as this is the first time I think I've even put it coherently to myself...

Behavioral evolution. The field of neuroscience contains the tools that most interest me in terms of searching for patterns in the evolution of behavior. The nervous system – central and peripheral – guides all the other systems of the body through interaction with the world. From the primitive neural web of the cnidarian to the ganglia of the higher animal, it is interaction with the world that makes us what we are. I love neuroscience for attempting to associate corporeal and ethereal phenomena. I love seeking out the physiological correlates of consciousness, and the pathological correlates of behavioral dysfunction. I crave the abstraction of physiology into a medium for mind and consciousness. My own autonomic system excites when connections are made between the evolution of that medium and the evolution of the intelligence it propagates.

on the changing face of science

I was inspired to pursue academic science by Santiago Ramon y Cajal, the man who discovered neuroplasticity. He was an academic, but first, a scientist and artist. At the end of the first book I read of him was his epitaph, which became the source of my conviction that real science, unfettered by the politics of academia, still exists.

"Scientists should be adventuresome people, restless and imaginative. They should be generous souls - poets at times, but always romantics - and they have two essential qualities. They scorn material gain and high academic rank, and their noble minds are captivated by lofty ideals."

In this process of bolstering my curriculum vitae to attract graduate schools, I am inundated with the mean face of academic politics. It demands that I be recognizable within the scientific community before I am even part of it. Academia must be able to identify me as unique before they accept the burden of my education, but this uniqueness is rightfully represented only by my publications.

While I am the first author of several abstracts, I have not yet published any articles. And while being a first author before having a PhD is impressive, it is significantly less so than being a co-author on a published article. I have a qualm with this particular rule of hierarchy - and with Academia's perspective on publication in general. To be published as a co-author in a scientific paper, you need be involved as little as collecting a key piece of data without having any clue as to its importance to the paper itself. To be a first author, you are either the primary investigator (head of the lab) or you have performed/analyzed/written a substantial portion of the piece. The latter is my case.


I recently mined a book on this subject by Thomas Bender, Intellect and Public Life: Essays on the Social History of Academic Intellectuals in the United States. Among other discussions is that of Academia's role in determining the evolution of science by publication, and how scientists are evolving to become defined by the magnitude - quality and quantity -of their publications instead of their contributions to scientific stride through their careers.

In Cajal's day (the late 18- and early 1900s), publication was a serious achievement, like Galileo's 550 printed copies of The Starry Messenger. Today, it is not unusual to expect an undergraduate student to have their name planted among a list of authors on a paper or two. This is a blessing and a curse. The circulation of scientific discovery has skyrocketed to a point where many articles are freely accessible to the public. However, credit for scientific discovery has become such a bilious diatribe that publications include up to ten co-authors, and the tiniest inkling of participation in the tiniest piece of the article gets your name on the list. Students are recruited to graduate schools based on their publications. Academic scholars are recruited to run labs based on quantity of publication alone, which may or may not sound absurd only to me. The physicist Richard Feynman was asked to head an engineering lab at Princeton because his name was on an unapplied patent that came out of Los Alamos. During the war, Los Alamos was flooded with some of the brightest minds in physics, and the opportunity was taken to exploit any random idea that popped into their heads. A lot of cool shit went down at Los Alamos.


I can't fairly condemn the evolution of publication's importance to Academia, nor Academia's reliance on publication to determine the worth of a scientist. My hope, however, is that quality does not become lost in quantity. I hope that my curriculum vitae communicates that my lack of publication does not represent my throughput or ingenuity...

I have spent over two years with my boss developing a huge project which has evolved from my own undergraduate thesis. The process has involved a scrupulous amount of project design, methodology, animal model development, endless amounts of research and, as goes without saying, an infinite amount of experimentation. As we have been too busy writing grant proposals and collecting alternative data, we have not yet published anything on the many results of this project. Fortunately, my boss has offered me the opportunity to co-author on a textbook chapter and set aside time to write an article on the novel mouse model I have developed before I submit my graduate applications. My boss reminds me of Cajal.

I maintain, sanguinely, that many graduate institutions still have the integrity to investigate the entire portfolio of a scientist before deeming woth investment. That ideal, however, may prove to be too lofty...

on the roles of science

I've been thinking about how the role of scientific endeavor has morphed since the Scientific Revolution. What it's value has been, and what it has become.

One of our current controversial quests is to take advantage of what opportunity stem cells hold. Is the aspect of reality at stake here as great as that of Copernicus' heliocentric system or Giordano Bruno's infinite universe? Sciences battle with the church exists in the stem cell revolution, but is it as prevalent and restrictive as was the Roman Inquisition? The obvious answer is that no, it is not. Science has an easier time evolving in modern society because our paradigm since the Scientific Revolution has been to encourage the pursuit of knowledge. Since the breakdown and reconfiguration of the Church, theory has become a more friendly phenomenon. Theory then evolves into science much more naturally and with less turbulence. Scientific discovery glides into public gaze with less suspicion.

There are more scientists and, as such, more reason for the public to accept that what the scientific community promulgates. This is something that Thomas Kuhn does not talk about, and I wish he would have. He considers the role of individuals within the scientific community who are more bold than others, and who stimulate acts of revolutionary science. The roles of the other community members, however, are somehow uninteresting to Kuhns concepts.

The role of the scientific community, I think, is to speed up the process of insight. The scientific body gravitates toward one emerging framework or its opponent with the same outcome as the battle of superseding geniuses against the Roman Inquisition. Internal discordance now slows the progress of science instead of the fear of a shift in reality or religious allegiance. It's no less turbid than pre-Revolution, but certainly more urbane... there is no sabotage or torture in modern Science. I actually think that by handing the beast to itself, the Church has simply backed away from the recidivism of the tyrannical father and become the comforting grandmother to those who can't handle theoretical threats posed to reality.

So has it become easier for science to thrive since the Revolution? Yes. Has new knowledge become globally welcome instead of globally feared? To those territories who experienced a Scientific Revolution, yes. Has the quelling of that global fear opened new doors for the free emergence of scientific revolution? Perhaps.

Does revolutionary scientific discovery hold the same earth-shattering importance that it once did? Not really.

Does an individual scientist suggest as much importance to the growth and sustenance of the world as they did during the Renaissance? Well...

I like to hope that we do. But I will need more convincing as my career proceeds.

aspirin and parkinson's

arachidonic acid is one of the reasons that a high meat diet contributes to early neurodegeneration - it's not just about caloric intake, it's about the amino acids you accumulate. arachidonic acid is a fatty acid precursor to prostaglandins, which are made in excess when neurons die and release arach. acid into the extracellular system, or when introduced in excess through extensive meat intake.

Aspirin inhibits prostaglandin production. inhibited prostaglandin production releases less arachidonic acid to oxidize other cells. less arach. acid allowed to do damage over time decreases the chances of developing Parkinson's disease.

take Aspririn (or any NSAID, really) to avoid PD when you're eighty. but also, eat less fatty meat.

empty thoughts IV

4. Whyyyyyyy is it obvious that because autistic children have an impairment in only a particular type of reasoning that one type evolved separately from the other? Explain to me how this is in any way a solid framework to make this broad of a conclusion with any certainty.