closer to home

writing my last few posts, i've discovered that it's awfully hard to explain broad physiologic principles in just a couple paragraphs. not only that, it's a bit of a waste for me to regurgitate concepts that i'm already familiar with, just for the sake of continuity. so i'm gonna scratch that plan and go back to what worked before my comp--sporadic, on-demand posts. at first i was worried that i wouldn't have enough material to untangle, but now, in retrospect, that was a rather hubristic concern. there are more than enough relevant--albeit random--questions that pop up in the course of my day, so i'll address those instead in this space.

so, where better to begin than my current laboratory project. here's the idea (as always, i will try to make this palatable):

as i mentioned before, there's been a shift in thought regarding coronary artery disease (CAD), from a paradigm of progressively clogged vessels to the current understanding of arterial inflammation. arteries, it turns out, become inflamed as the result of what i like to call "molecular irritants," e.g. cholesterol, fats, etc, the same way a mosquito bite becomes red and swollen after you scratch it. there is still clogging and narrowing of arteries, but these deposits alone do not cause, say, a heart attack. rather, inflammation of arteries renders these deposits unstable, causing them eventually to break free and float downstream until they clog a narrow vessel like a coronary artery.

as a result of this new understanding, inflammation has become an attractive target of research. my project concerns the effect of the nervous system on inflammation. (a quick fyi on the autonomic nervous system: there are two pathways that govern your body's reflexive response to stimuli--sympathetic and parasympathetic. sympathetic activation is the famous "fight-or-flight" reflex. parasympathetic activation is the opposite.) it's been shown that parasympathetic stimulation results in decreased activation of an important inflammatory cell--the macrophage. specifically, a receptor for the parasympathetic neurotransmitter acetylcholine resides on the surface of macrophages, and it's also been shown that mutations in the alpha-subunit of this receptor results in a loss of the anti-inflammatory effect imparted by parasympathetic activity. furthermore, these mutations have been characterized at the DNA level, so that the specific genetic sequence underlying each of these mutations is known.

my hypothesis, then, is that these genetic variations, because they result in a loss of anti-inflammatory "protection," may be found in those patients who suffer from premature CAD. for the past ten years, the cleveland clinic has been assembling a database of CAD patients' genetic profiles. using that database, i'll be sequencing the macrophage receptor alpha-subunit gene (the promoter for the gene, to be precise) and looking for a statistically-significant prevalence of gene mutations compared to a population of normal control individuals. nothing too complicated--just an old fashioned case-control association study.

if i'm violating some kind of unwritten rule, where one can't divulge your research interests until publication, i apologize in advance... to no one.

what's most importantly

the neuromuscular junction is just that: the junction between a nerve ending and a muscle fiber. let's say this particular nerve originates in the brain, and the target muscle fiber is an abdominal muscle. now, let's also say you're sitting in your room, listening to kanye west's new workout plan, and you decide hey, i should do some crunches. you lie down, and a split-second before you crunch, the following happens (very roughly speaking):

first, your brain sends an electrical signal--an action potential--down the length of the nerve towards the neuromuscular junction. the action potential doesn't move uninterrupted along the nerve like an ocean wave, however. instead, it's more like a relay race runner, moving a short distance before initiating a consequent, identical action potential, which then does the same. another way to think of the action potential is as the baton in a relay race. either way, this relay race of action potentials eventually hits the nerve ending, aka the nerve terminal, where the key electrochemical process begins.

one of the more remarkable aspects of cell physiology is the conversion of electrical to chemical energy, and vice versa. in the case of the neuromuscular junction, the action potential causes voltage-gated (i.e. voltage-sensitive) calcium channels to open up. calcium then rushes into the nerve terminal, dramatically changing the ionic milieu of the cytoplasm (each calcium ion carries a 2+ charge). this results in the fusion of tiny vesicles to the plasma membrane, each one containing a certain quantal amount of acetylcholine (ACh), a neurotransmitter. a graphic but effective way of visualizing this release of ACh is to imagine each vesicle as a free-floating uterus containing a baby named ACh. upon depolarization by the action potential, these vesicles move to the nerve terminal and "give birth," releasing the ACh baby to the extracellular world. ok bad metaphor, but it's friday night and i'm about to head out.

anyway, the ACh then moves across the space between the nerve terminal and the muscle fiber--the synaptic cleft--until it reaches the receptors for ACh, called nicotinic receptors (named for their specific reponse to death. i mean cigarettes. i mean nicotine). these receptors are special for all kinds of reasons that i won't get into here. suffice it to say, what's most importantly is that ACh is the indispensable errand boy of all voluntary muscular contractions. botox, for example, blocks the release of ACh, preventing muscle stimulus and thereby also preventing all the muscle activity that leads to wrinkles and such. but, with the appropriate transduction ACh, you can happily do your crunches and eventually score an nba player like kanye says.

cavalier

right now i'm watching game one of the nba finals. detroit has to be one of the most underrated teams in professional sports history. who's given them any respect in the past two years? detroit's only up 27-24 right now, but even if san antonio goes on to win the series, detroit, in my mind, has earned its wings as one of the great nba teams of the past 25 years.

although they're primarily known for their stingy defense, one of the pistons' hallmarks is its "flex" offense. many teams employ a flex offense, including my beloved university of maryland terrapins, particularly when they feature quick, accurate-shooting guards like juan dixon or, detroit's star guard, richard hamilton. you'll often hear the word "curl" and "rotation" associated with flex offenses. the guard moves in a circle about 15 feet from the basket, running through screens to get open for a mid-range jumpshot. drawn up with x's and o's, a flex offense is a bunch of curved arrows.

in cell physiology, the transport of molecules and ions across cell membranes is often facilitated by so-called transport proteins--integral membrane proteins that allow specific substances to pass in and out of cells. some of these transport proteins need a direct burst of energy to move an ion, for example, across the membrane. the most ubiquitous of these primary active transport proteins is the sodium-potassium pump, aka Na+,K+ ATPase. this ATPase is present in all cell membranes, and it pumps three Na+ ions out of the cell and two K+ ions into the cell. the way my simple brain remembers this is, "Na+" is 3 characters, so 3 sodium ions are pumped out, and "K+" is 2 characters, so 2 potassium ions are pumped in.

another important concept in characterizing transport and receptor proteins is the subunit building block. the Na+,K+ ATPase consists of an alpha and a beta subunit. the alpha subunit is the busy subunit, responsible for the ATPase enzymatic activity (-ase = enzyme) and the binding of both sodium and potassium. likewise, my current research involves examining the gene that codes for an alpha subunit of a nerve receptor. as you can probably deduce from its functions, the Na+,K+ ATPase alpha subunit isn't static--it moves in order to shuttle ions across the plasma membrane, changing shape depending on what's bound to it. specifically, when Na+ binds to the ATPase from the inside of the cell, the enzyme then undergoes a conformational change and rotates to the extracellular (outside) surface of the membrane, where it then releases the sodium and binds a potassium in exchange.

hence the flex offense and the curl. at least for me, thinking of transport proteins as dynamic, shape-shifting entities helps me understand both their functions and their roles better, rather than simply thinking "ok, Na+,K+ ATPase is 3 sodium out, 2 potassium in." like rip hamilton, the ATPase starts from one end of the membrane "court," rotates across to the other end, and releases the shot. it's not the best metaphor--whereas the ATPase alpha subunit carries the Na+ ion, hamilton moves without the ball. but whatever.

oh, and i almost forgot: cavalier! back in high school, my lacrosse team ran a cool play called cavalier, named after the university of virginia mascot. when coach called cavalier, the midfielder with the ball (me) stood up top--think the top of the key in basketball--while the three attackmen ran in a circle in front of the goal, waiting for a pass for a quick score (kinda like a flex offense). unfortunately, the play never worked in a game, but at least it always looked cool.

bada bing!

made again famous by the sopranos, sonny corleone uttered these famous words after his little brother delivered the monologue that i consider to be the turning point of michael corleone in the godfather. some people point to michael's tender moment at his father's bedside in the hospital; others say it's when he pulled the trigger on sollozzo and mccluskey in louis' restaurant; a strong case can also be made for apollonia's death by car bomb, which presumably sealed michael's fate to a life of violence.

but no, my favorite scene is when michael is sitting in a chair, one leg crossed over the other, simultaneously thinking through and explaining his plan to prevent sollozzo and mccluskey from ever harming his father again. that, i think, was when he irreversibly committed himself to the family, and his monologue--with the slow zoom in on his busted jaw and his droopy eyes--marks the first of his many calculated, cruel masterstrokes of vengeance. it is the beginning of his end.

that's how i like to think of heart disease. the beginning of the end. research shows that coronary arteries start narrowing not at 30 or 40 but at childhood. everyone, it appears, has some baseline degree of heart "disease." but what is it that causes heart disease--specifically, disease of the coronary arteries (CAD), the arteries that supply the heart with blood? is it the infamous things--high blood pressure, high cholesterol, obesity, smoking? how about family history, or IV drug use? or is it something else? my summer research has to do with how heart attacks are inherited, strange as it may sound. after AP bio and bs50 and bs52 and bs57 and the first-year genetics committee, i have a decent handle on how genetics works and the molecular machinery that results in a heart attack gene moving from one generation to the next. what i don't really understand, though, is how CAD works, i.e. its pathogenesis.

it turns out no one else really knows how it works either. as recently as the early 1990s, many physicians and researchers still believed that, if they could eliminate high blood pressure and high cholesterol, the elimination of CAD would follow. unfortunately, CAD isn't so simple, and its pathogenesis is now largely understood to be a complicated inflammatory process. allow me to be a shameless dork here and say that i think inflammation is fascinating. inflammation can be good, can be bad, can be seen and felt, can be invisible and silent, can be acute, can be chronic... it can do pretty much anything, anywhere (think of all the -itis diseases you've heard of. arthritis, gastritis, conjunctivitis, etc. even elephantitis, although not glorified like eminem would have you believe). now it seems it can even result in CAD and heart attacks.

all this brings me back to two of my least favorite subjects--basic cell physiology and immunology. these are the two biology fields that absolutely and obscenely adore using senseless numbers and letters to name things. unsurprisingly, these were the two subjects with which i struggled most last year. and, also unsurprisingly, cell phys and immunology are the cornerstones to the heart disease inflammatory process.

therefore, tomorrow i'll begin with a review of cell phys, using my beloved costanzo review book as my guide. i'll then move through the different organ systems, although slightly out of order so that i can do heart and vasculature first and thereby provide at least some semblance of narrative continuity throughout this summer's posts.

"it's not personal, sonny. it's strictly business."

the emancipation of albert

a washed-up, old, completely insane mariah carey still has more talent in one alveolus than 99% of recording artists out there today.

busy day. will post for real starting tomorrow.

in the summer, in the city

after a much-needed week at home in merryland, tomorrow it's back to cleveland for a summer of work. lots of people have asked me why, for this, my last free summer ever, with the chance to go anywhere i want, i decided to stay in cleveland. sometimes, i wonder the same thing. but right now i'm excited to go back. i have a sweet sweet job waiting for me--an exciting project on the genetics of heart attack. and now, unlike earlier this year when i started the project but was utterly lost, i have a handle on the basic physiological processes--hemodynamics, cardiac function, inflammation--that underlie my research.

in other words, like the detroit pistons, i say, "bring on the heat." it'll be nice to experience the working life for a change. 9-to-5 weekdays, carefree weekends, no studying constantly hanging over my head. but, masochist that i am, i'll be updating this blog daily again, mostly with reviewed material from the past year. also, now that i'm no longer haphazardly studying for my comp exam, i'll be reading up in a more organized fashion, so my posts should make more sense from one day to the next. or at least the actual medical content will. my metaphors and mnemonics, on the other hand, will likely become bizarrer and bizarrer. after all, this blog is still all about me and me trying to learn my stuff. ya'll will just have to deal.

yay? yay.

the man who fell out of bed

i met oliver sacks in high school, at the now infamous "arizona thing." towards the end of senior year, i was invited--along with 400 or so other high school students--to an all expenses-paid 4-day vacation at the phoenician resort. there, we students had the opportunity to cavort with america's rich and famous. lauryn hill, gen. wesley clark, arthur golden, ben carson, 23 nobel prize winners... it was surreal, to say the least. below is a photo of me and composer john williams. nice guy, although not as tall as i'd thought.


me with the man 

anyway, oliver sacks was there too, and at the time i had no clue who he was. i didn't know yet that i wanted to be a physician, and dr. sacks struck me as more odd than inspiring. he mumbled and stuttered throughout his speech, his eyes fixed on his feet, and he wrote books with strange titles like the man who mistook his wife for a hat. what a freak.

but, five years later, almost to the day, i've picked up his book and found it to be absolutely mesmerizing. i still only have a rudimentary grasp of the biology with which he's concerned--i know the left and right brain stereotypes like anyone else, and i know how strokes and brain tumors come about. but it's enough for me to appreciate some of the stories he tells. his patients are extraordinary--a man who, yes, mistakes his wife for a hat, a woman who has no sense of "left" (think derek zoolander's ambi-turning deficiency, but without the humor), and a man with memento-style amnesia. human consciousness is one of those black boxes that never really piqued my interest--i'm perfectly happy not knowing how it works, so instead my professional interests, i assumed, would concern diseases with less metaphysical weight. still, dr. sacks' book makes me wonder...

here is an excerpt:

Thus, in one patient under my care, a sudden thrombosis (clot) in the posterior circulation of the brain caused the immediate death of the visual parts of the brain. Forthwith this patient became completely blind--but did not know it. He looked blind--but he made no complaints. Questioning and testing showed, beyond doubt, that not only was he centrally or 'cortically' blind, but he had lost all visual images and memories, lost them totally--yet had no sense of any loss. Indeed, he had lost the very idea of seeing--and was not only unable to describe anything visually, but bewildered when I used words such as 'seeing' and 'light.'... His entire lifetime of seeing, of visuality, had, in effect, been stolen.