Monthly Archives: March 2013

Scientists Got Jokes, Y’all* (Humor guide included within)

I found this image a few weeks ago while submitting an abstract for ICRS2013, this year’s research conference of the International Cannabinoid Research Society.  It’s a sample abstract meant to illustrate the format we were to use for our own.  At first glance I thought it was a real abstract from a past meeting, but closer scrutiny revealed something unexpected: it’s a parody!  And a very well-executed one.

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For the uninitiated who would hate to feel left out of the joke because of its wry subtlety (as I certainly would feel), here’s a brief glossary of terms in the order they appear:

ICRSin – Names of biological molecules often end in -in (e.g. actin, serotonin, bradykinin).  ICRS is the society sponsoring the conference

Anan D’Amide – The name of the abstract’s first author is a play on anandamide, a signaling molecule produced by cells that then binds to cannabinoid receptor proteins–the same receptors activated by THC, the active drug in cannabis.  Ananda is actually a Sanskrit word meaning “happiness” or “bliss” (heh heh… silly stoner scientists), and behavioral research shows an anxiolytic/antidepressant effect of anandamide.  Plus, Anan itself is a name, and surprisingly, it looks as if Amide may be a real surname!  All-around excellent pun.  Truly Joycean.

Thomas H. O’Cannabinol – A play on THC, which stands for tetrahydrocannabinol.  Not as good a pun as the one above because the Google machine can’t locate anybody with the family name O’Cannabinol.

Too A. Gee – A play on 2-AG, which stands for 2-arachidonoylglycerol, another biological signaling molecule that, like anandamide, targets cannabinoid receptors.

University of Endoca, Nabino, ID, USA – Anandamide and 2-AG are endogenous (found naturally in the body) cannabinoids, or endocannabinoids.

WIN-CP cells – WIN and CP are common abbreviations for the synthetic drugs WIN55,212-2 and CP55,940, which are both cannabinoid receptor agonists like anandamide, 2-AG and THC, but are not naturally occurring.  They’re also much more potent than the naturally occurring cannabinoids, with effects that don’t sound very pleasant according to anecdotal reports.  Side note: drug names often begin with an abbreviation for whatever pharmaceutical company invented them, followed by an identification number.  WIN = Winthrop, which was acquired by the French company Sanofi, and CP stands for Charles Pfizer.

2% ethanol – Ethanol of course means alcohol, but I’m puzzled as to why the “experimenters” used such a low concentration.  Beer is typically 3.5-5% ABV and wine is 10-14%.  Both must be present if the authors are to replicate previous meeting conditions.  If I were a reviewer of this abstract I would ask for clarification before accepting it.

pro-vost, a well-known toxic agent – Can most people in academia attest to this?  I’m not sure. Biological molecules are formed from precursor molecules, which often include the prefix pro- (and can be active themselves, usually in a different way from their final synthesized products).

creativase, beauracratase – Enzymes, proteins that selectively catalyze biological reactions, often end in –ase (but not always).  I suppose the respective decrease and increase of these enzymes’ activity makes sense in the presence of pro-vost.

referee who just doesn’t understand (RWJDU) – ICRS is headquartered/based out of Research Triangle Park, NC.  College basketball is kind of a big deal in this state.  But not anymore at Wake Forest, which is coached by Jeff Bzdelik.

Consider me impressed! And that’s not all: the organizer for this year’s meeting sent us a fantastic reminder email invoking Julius Caesar, the Ides of March and Shakespeare:

Dear [_______],

Although tomorrow and tomorrow and tomorrow may creep in a petty pace from day to day, the 2013 ICRS abstract submission deadline (March 15) is HERE.

Be aware, the Ides of March is today! 

The ICRS will be pleased to accept your abstract for the 23rd annual meeting, to be held June 22-25, until tonight at MIDNIGHT.  Julius Caesar ignored the soothsayer’s warning to beware the Ides of March and look what happened to him: He could no longer submit his ICRS abstract!  March 16 was too late for this Roman general and statesman to submit his abstract and it will be too late for you, too.  Although abstracts and travel award applications will not be accepted after March 15, the registration and accommodations site will remain open until May and on-site registration is possible.

With my sincere apologies to Shakespeare,

Jenny L. Wiley, Ph.D.

President, ICRS

Something like this would never appear in anything associated with HBPR (High Blood Pressure Research), the other major annual conference I attend.  The difference in formality between the two is stark.  Hypertension researchers tend to be all SRS BSNSS, while cannabinoid scientists are incredibly laid-back (shocking, I know).  I think there’s a parallel to marriage here, something about two people starting to resemble each other after being together long enough, but applied to scientists and their focus area.  I wouldn’t know, but you can guess which meeting I’m more looking forward to attending this year.

A Brief Introduction

This post dates to last October, but I thought it would be worth re-posting over here since I’ve migrated in that time.  It’s an extended abstract of my research project that I submitted to the Charlotte Life Sciences conference last Fall.  I was among ten finalists selected from a pool of 20 regional universities to present our work to a panel of scientific advisors, business strategists, and private equity investors.  I doubted I had much of a shot of winning the $1,000 first place prize, but it did allow me to write about what exactly I study in a language that people outside the ivory tower (mine is actually brick) can somewhat understand.  Which is sort of exactly what I’d like to do with my career, only to a much greater extent than how it is “simplified” below.

I’m posting my introduction here mostly for posterity.  It’s fleshed out way more than it would be for my usual audience of cardiovascular scientists.  However, I am exceedingly proud that my former theatre major friend kind of understood what I wrote with the help of a few definitions.  If you’re particularly curious and/or bored, feel free to read on and learn how some of your tax dollars have been used the past few years:

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Endocannabinoid Modulation of Baroreflex Sensitivity in a Model of Renin-Angiotensin System-Dependent Hypertension

As of 2012, one in 3 U.S. adults is hypertensive, defined as having a resting blood pressure greater than 140/90 millimeters of mercury.  While hypertension itself is asymptomatic, the statistics of cardiovascular diseases are startling: 69% of patients with a first heart attack, 77% with a first stroke, and 74% with congestive heart failure are hypertensive.  In 2008 the estimated direct and indirect cost of managing high blood pressure, including medications, doctor visits and hospital admissions, was $50.6 billion, up from $43.5 billion the previous year.  Hypertension thus represents a massive health and economic burden.

Despite significant advances in the ability to manage high blood pressure, its root causes remain elusive.  The two components of the autonomic nervous system, the sympathetic and parasympathetic nervous systems, have emerged as prime research targets for their role in blood pressure regulation.  Hypertension is usually accompanied by an autonomic imbalance in which the sympathetic nervous system predominates over the parasympathetic branch.  Some direct consequences of this imbalance include elevation of circulating sympathetic hormones, increased blood vessel constriction, increased heart rate, and reduced baroreflex sensitivity.

The impairment of baroreflex sensitivity (BRS) for control of heart rate, measured as the reduction of heart rate in response to increases in blood pressure, often precedes the onset of hypertension.  The arterial baroreflex is the primary feedback control system for the short-term regulation of blood pressure and is an important indicator of vagus nerve function.  The effectors of the baroreflex are the baroreceptors: stretch-sensitive mechanoreceptors concentrated in the walls of the aortic arch and carotid sinus that can detect changes in blood pressure.

Baroreceptors are innervated by fibers of the vagus and glossopharyngeal nerves, which make their first synapse at the solitary tract nucleus (NTS) of the brainstem, a major autonomic integration center.  When arterial pressure increases, baroreflex afferent neurons transmit excitatory signals to the NTS.  The NTS will then increase downstream activity of the vagus nerve, yielding a decrease in heart rate to help return blood pressure to resting baseline.  Therefore, identification of biological factors that may influence BRS is critically important for understanding the development of hypertension and other negative cardiovascular outcomes.

Tonic upregulation of the endocannabinoid system, endogenous compounds that act at the same receptors as marijuana, is strongly associated with hypertension and its risk factors.  The endocannabinoid system is a ubiquitous cellular signaling system that modulates cellular activity in peripheral organs and the central nervous system.   CBcannabinoid receptors, the principal neuronal target of the endocannabinoids, are densely expressed on nerve terminals in the NTS.  Previous studies show cannabinoid ligands, such as delta-9-THC and the endogenous cannabinoid anandamide, can modulate neuronal activity within the NTS via CB1 receptors.  Therefore, we hypothesized that activation of NTS CBreceptors would alter BRS for control of heart rate in live, normotensive Sprague-Dawley rats.  We further hypothesized that we would find evidence of upregulated CBreceptor tone in the NTS of a monogenetic model of hypertension, the (mRen2)27 rat, contributing to impaired baseline BRS in this strain.

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Essentially, I study how marijuana-like molecules in your brain affect your body’s control of blood pressure and heart rate.  And if you’re wondering, yes, smoking up chronically does interfere with your body’s ability to do this.  If you’re also wondering, no, I do not have access to weed in the lab. (That’s the most common question I get asked at conferences)

Lit Review: Consciousness: Confessions of a Romantic Reductionist

A truncated version of this post first appeared in issue 14 of The Neurotransmitter

Consciousness: Confessions of a Romantic Reductionist

Christof Koch

MIT Press (Cambridge, MA), 2012

Bart: What is the mind?  Is it just a system of impulses or is it… something tangible?

Homer: Relax.  What is mind?  No matter.  What is matter?  Never mind!

– The Simpsons, “Good Night,” 1987.

The nature of the mind is a philosophical topic as old as philosophy itself.  Plato, Aristotle, Descartes, Kant, and other historical thinkers shared ideas about the mind that remain influential today.  Many of these ideas laid the foundation of modern neuroscience, as scientists established that the mind is a product of the brain.  To understand the mind we must therefore understand the brain, and this has proven to be one of the greatest challenges science has ever encountered.

There was intense debate late into the twentieth century about whether it was even possible to study the physical relationship between the mind and the brain.  Out of this debate emerged a new problem dealing with consciousness: what must happen in the brain for our awareness of the world to arise?  And more importantly, why do these internal brain events cause us to experience the world around us?  This so-called Hard Problem of Consciousness attracted scientists from the burgeoning field of cognitive neuroscience in the 1980s and 90s, with Christof Koch of the California Institute of Technology among them.  While working closely with his friend and mentor Francis Crick—the co-discoverer of the double helical structure of DNA—Koch became one of the pioneering neuroscientists in the study of consciousness during a time when most considered it a fringe subject.  In his book Consciousness: Confessions of a Romantic Reductionist, Koch offers a personal account of his life’s work and his goal of understanding the origins of the mind.

The opening chapters of Consciousness relay some anecdotes that helped shape Koch’s scientific quest.  Here he manages to portray himself as someone many in science can relate to: an earnest, romantic nerd.  The content of some passages may border on the mundane, but the tone of Koch’s writing is kept refreshingly personal, reminding readers he is a flesh-and-blood creature with real motives and desires.  These chapters are indeed a large reason for the book’s subtitle Confessions of a Romantic Reductionist.  Koch’s “confession” is that he was drawn to the study of consciousness by his desire to justify his instinctual belief that life is meaningful. “By giving the study of consciousness my all and failing in this endeavor, I was going to demonstrate to my own satisfaction that science is inadequate to the task of fully understanding the nature of the mind-body divide.”  He concludes his confession with an enticing spoiler: “In the end, this is not how it turned out.”

Religion played a very influential role in motivating Koch to become a scientist, and he emphasizes its importance to his childhood in the book’s endearingly candid second chapter.  The liberal, though devout, Catholic tradition in which he was raised provided a framework for fulfilling his curiosity about the natural world that was both intuitive and comforting.  But as Koch grew older it became more difficult for him to reconcile his religious beliefs with the naturalistic stance of his profession.  He admits to an internal conflict between faith and reason that persisted well into his career, and was resolved only in recent years by abandoning his belief in God.  However, a pervasive theme in Consciousness is Koch’s view that there must be something grander in the laws of the universe that science has not yet fully illuminated.  He projects a sense that his religious conviction is not quite fully lost, and whatever remnant he retains is in part driving his research.  As he says, “I lost my childhood faith, yet I’ve never lost my abiding faith that everything is as it should be!  I feel deep in my bones that the universe has meaning that we can realize.”

Despite his apparent reluctance to fully divorce himself from his Catholic background, Koch is still foremost a scientist and demands evidence.  “Let the conversation turn to consciousness, and everybody chimes in, on the assumption that they are all entitled to their own pet theory in the absence of pertinent facts.  Nothing could be further from the truth,” he forcefully asserts, as if to reassure wary, scientifically minded readers.  The central argument Koch makes is that modern neuroscience now possesses the tools to investigate consciousness, therefore elevating its status from fringe or pseudoscience into a legitimate scientific field of inquiry. Koch’s and Crick’s own research focus is in what they termed the “neural correlates of consciousness”—the minimum neuronal activity sufficient to generate a specific conscious percept—and they probed the primary visual pathway in search of these.  He makes it clear, however, that they are far from the only scientists at work.  Much attention is given to Naotsugu Tsuchiya’s work with fMRI and the technique of continuous flash suppression.  Later chapters describe case studies by neurologists on peculiar perceptual defects like prosopagnosia (face-blindness) and akinetopsia (motion-blindness), as well as the brain’s subconscious “zombie agents” that control much of our lives from beyond our awareness.  The discussion of consciousness progresses from practical to theoretical when Koch introduces neuroscientist Giulio Tononi and his Integrated Information Theory, praising it as the most promising fundamental theory of consciousness yet.

Perhaps the most fascinating parts of Consciousness are in its seventh chapter, in which Koch “throws caution to the wind” and expounds upon one of the more abstract concepts to emerge with the study of the mind: free will.  The question of whether humans are truly agents of free will has tormented philosophers for centuries.  The intuitive answer to most is of course we have free will, meaning the power to behave and make decisions of our own volition.  René Descartes was a strong proponent of this view, as was Koch as a younger man.  Remarkably, data from modern neuroscience refute this classical notion of free will.  Koch points to the work of physiologist Benjamin Libet, who famously showed that EEG can detect activity in the motor cortex, called a readiness potential, up to half a second before a person feels the decision to initiate a movement.  Further compelling work by psychologist David Wegner seemed to confirm these results, and convinced Koch to adopt a new position on free will.  Nevertheless, he stops short of believing that behavior is fully determined by physical laws using what some readers may consider specious reasoning.  He cites the chaotic orbit of Pluto, which makes it impossible to predict its future position along its orbit, along with the quantum uncertainty principle as proof that natural laws are inadequate to account for all human behavior.  What Koch does not mention is that Pluto’s orbit is chaotic largely because its tiny mass (in relation to the other planets of the Solar System) precludes it from clearing its orbit, leaving it forever vulnerable to the perturbations of as-yet unseen, distant objects.   Nor does he offer any insight into whether quantum indeterminacy does or does not measurably affect behavior.  Even so, Koch is by no means a minority figure as a prominent holder of a compatibilist view of free will (Daniel Dennett readily comes to mind), and his thoughtful treatment of the subject is among the best qualities of Consciousness.

Koch’s discussions of the science avoid sounding pedantic and mostly tie into the theme that small chunks of gray and white matter are responsible for encoding very specific pieces of conscious content.  Readers lacking an introduction to basic neuroscience may struggle with these segments of the book, but Koch lucidly conveys the significance of these discoveries to his target audience, with a palpable sense of excitement.  One shortcoming of the book, however, is the deficiency of new perspective Koch offers with respect to the science he describes.  It often seems as though the opinions he expresses are non-committal or incipient, especially toward his personal feelings on the relationship between science and religion, but this may simply be his inner scientist revealing itself to readers.  Broaching subjects as personal as these, considered off-limits to formal scientific discourse, certainly requires a degree of bravery, just as embarking on a quest to understand the nature of consciousness once did.  On this topic, Koch is perfectly clear: thanks to the tools of modern neuroscience, we are much further along in the study of consciousness than Plato, Descartes, Kant, and Homer Simpson ever were.  Overall, Consciousness: Confessions of a Romantic Reductionist is an engaging, succinct introduction to the study of the mind by someone who should be easily relatable to many young scientists and students of neuroscience.

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PET Scanning Reveals Neurodegenerative Condition in Retired NFL Players

A version of this post first appeared in issue 14 of The Neurotransmitter

Junior Seau was one of the most decorated and beloved players in the National Football League (NFL) over an iconic professional career that spanned twenty seasons.  As a linebacker, a bruising defensive position tasked with tackling offensive ball carriers, Seau’s honors included twelve Pro Bowl selections, the NFL’s 1994 Man of the Year Award, and being named to the NFL 1990s All-Decade Team.  He developed a reputation for his ferocious play and passionate on-field leadership, often playing through injury and performing a distinctive fist-pumping dance after big plays [1].  Most would agree that Seau was a wonderful representative of the NFL before retiring in January 2010.

On May 2, 2012, at the age of 43, Junior Seau committed suicide by a self-inflicted gunshot wound to the chest.  His ex-wife reported that he had suffered from depression and insomnia in the last years of his life [2].  Suspecting that brain damage related to his long playing career contributed to his suicide, Seau’s family donated his brain tissue to the National Institute of Neurological Disorders and Stroke at the National Institutes of Health (NIH) for analysis.  On January 10, 2013, his family announced that NIH neuroscientists had definitively concluded that Seau suffered from chronic traumatic encephalopathy (CTE) [3], a degenerative neurological condition associated with concussion-related brain injury.

Seau’s post-mortem CTE diagnosis is one of several high profile cases that have brought recent media attention to a disturbing trend among retired professional football players.  Studies of former NFL players reveal a persistently higher rate of personality and mood disorders (e.g. major depression), mild cognitive impairment (MCI), and severe dementia compared to the general population.  In fact, retired NFL players sustaining three or more concussions during their careers may be three times more likely to be diagnosed with depression and five times more likely to be diagnosed with MCI later in life [4, 5].  Dozens of similar cases in former athletes who had suffered repetitive brain injuries are linked to CTE after death [6, 7].

CTE manifests as a steady deterioration in mood, personality, motor function, and cognition.  It is confirmed by a variety of findings at autopsy, particularly the widespread accumulation of phosphorylated tau protein tangles (similar to Alzheimer’s disease), axon damage, inflammation, and other brain abnormalities, including neuronal loss [6, 7].  Clearly, CTE can be a devastating consequence of repeated traumatic brain injury, and it is quite alarming that so many people are at risk due to the popularity of contact sports [8].  That retired NFL players are disproportionately more at risk for CTE should be cause for further unease among current players and league officials.  After all, American football is not merely a contact sport, according to legendary coach Vince Lombardi—it’s a collision sport.

Despite the risk for CTE among former athletes, there is no established method for its early detection.  All cases of CTE are currently diagnosed at autopsy.  However, in a clinical research article from the February 2013 issue of The American Journal of Geriatric Psychiatry, Dr. Gary W. Small and his UCLA colleagues describe a promising method for the non-invasive early detection of CTE and similar brain pathologies [9].

Dr. Small’s group previously invented a new tracer ligand for use in positron emission tomography (PET) that is capable of detecting tau tangle deposits in living brains, and can track and predict cognitive decline in people without dementia [10, 11].  A PET scanner detects the energy released by the decay of a special radioactive isotope (called a tracer) that is injected into the bloodstream and selectively binds to a tissue of interest.  The energy released by the bound tracer is then rendered into an image and color-coded for signal intensity.  In their latest study, Dr. Small’s research team applied this PET imaging technique to the brains of five living, retired NFL players with a history of cognitive or mood symptoms.

The former players, ranging in age from 45 to 73 and having sustained between one and twenty concussions during their playing careers, completed a battery of neuropsychological tests prior to PET scanning.  The tests revealed that the players indeed have significantly higher depression scores than control subjects, as well as a trend toward lower global cognitive ability.  These results closely reflect the players’ clinical presentation, as three were diagnosed with MCI, and another with dementia.  All exhibited symptoms of major depression.

More distressing, however, are the PET scans of the players’ brains: all had very high tracer signal intensity compared to controls that was especially concentrated in the thalamus, midbrain and amygdala, indicating large tau deposits in these regions (see Figure 1).  These binding patterns are consistent with the tau build-up observed in autopsy studies of CTE [6].  Perhaps the most striking feature of the study is the illustration of a relationship between PET signal intensity and the number of concussions each player sustained throughout his career (Figure 2).  Although none of the correlations reached statistical significance due to the small sample size of players tested, the plots below show a clear trend toward an increase in tracer binding with more concussions suffered.

This study may have a considerable impact in medicine and sports.  The PET tracer developed by Dr. Small’s team could facilitate the early detection of trauma-related brain diseases like CTE.  As the authors note, the early detection of this condition is a crucial first step toward the development of medical interventions that may hinder the onset or progression of symptoms.  No such early detection method is currently in practice.  This study should also help raise further awareness of the substantial long-term consequences of traumatic brain injuries in many at-risk athletes.  The NFL is now placing a much greater emphasis on player safety [12], having recently adopted new playing rules, medical guidelines and equipment standards to reduce the health risks of the game.  Researchers at Wake Forest University and Virginia Tech are aiding this initiative by conducting research on football helmets to reduce the number of concussions suffered [13].  The effectiveness of these measures remains to be seen, but the goal remains that at the end of their careers, players can truly leave all of the game on the field.

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Figure 1 – Coronal and transaxial PET scans of retired NFL players show extremely high signals in cortical and subcortical brain regions compared to the control subject [9].

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Figure 2 – Plots showing PET tracer binding according to number of concussions sustained suggest a positive relationship between greater number of concussions and higher PET tracer signal in several brain regions [9].

References

[1] http://www.utsandiego.com/news/2012/may/02/chargers-greats-feats-on-field-and-off-spoke-for/?print&page=all

[2] http://usatoday30.usatoday.com/sports/football/story/2012-05-31/Junior-Seau-suicide-last-days-sleep-issues/55316506/1

[3] http://abcnews.go.com/US/junior-seau-diagnosed-brain-disease-caused-hits-head/story?id=18171785&singlePage=true

[4] Guskiewicz KM, et al. Association between recurrent concussion and late-life cognitive impairment in retired professional football players. Neurosurgery, 2005; 57:719-726.

[5] Guskiewicz KM, et al. Recurrent concussion and risk of depression in retired professional football players. Med Sci Sports Exerc, 2007; 39:903-909.

[6] McKee AC, et al. Chronic traumatic encephalopathy in athletes: progressive tauopathy following repetitive head injury. J Neuropathol Exp Neurol, 2009; 68:709-735.

[7] McKee AC, et al. The spectrum of disease in chronic traumatic encephalopathy. Brain, 2013; 136:43-64.

[8] Centers for Disease Control and Prevention: National Center for Injury Prevention and Control. Non-fatal traumatic brain injuries from sports and recreation activities—United States, 2001-2005. MMWR Weekly, 2007; 56(29):733-737.

[9] Small GW, et al. PET Scanning of Brain Tau in Retired National Football League Players: Preliminary Findings. Am J Geriatr Psychiatry, 2013; 21(2):138-144.

[10] Shoghi-Jadid K, et al. Localization of neurofibrillary tangles and beta-amyloid plaques in the brains of living patients with Alzheimer’s disease. Am J Geriatr Psychiatry, 2002; 10:24-35.

[11] Small GW, et al. PET of brain amyloid and tau predicts and tracks cognitive decline in people without dementia. Arch Neurol, 2012; 69:215-222.

[12] Cf. http://www.nflevolution.com/

[13] http://www.news-medical.net/news/20130130/Wake-Forest-expands-football-helmet-research-to-reduce-sports-concussion-risks.aspx