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a common mistake one hears when engaging students early in their studies of neuropharmacology is a faulty assumption of distribution. you might ask them how we know that brain region x is involved in process y, and how one could test that. and you might get the answer that they would use a drug that targets “only brain region x” to test their ideas.
i smile when i hear this answer, because it’s a great lead-in for discussion of a basic neuropharmacology principle:
if it got into your brain through the blood-brain barrier, it’s everywhere in the brain. not just in your area of interest.
this has presented us with major challenges in terms of neuroscience drug development. a given molecule hanging out in the brain will bind to whatever it will bind to, and it doesn’t really care whether it’s in the hippocampus or the nucleus accumbens while it’s doing the binding.
it’s like throwing a drop of food dye in a glass of water, hoping only to color the water on the top. you can’t stop the dye from distributing around to the bottom of the glass as well. it’s soluble in the water, it will distribute through all of the water. a CNS-active drug is generally hydrophobic (or fat-soluble) to have made it through the blood-brain barrier, so it will distribute quite well throughout the entirety of the membranes of your brain.
we have all kinds of common elements throughout the varying regions of the brain- we do not have receptor H only in the hippocampus and receptor N only in the nucleus accumbens. brain function is achieved using many receptor types which are redundantly expressed in many different brain regions. if your receptor target is expressed in 12 brain regions, your drug will hit receptors in all of those regions, and may alter brain function in all those regions.
also consider that the regions all tend to be involved in different processes. now it becomes apparent that we could go in to correct a malfunction that affects one region, with undesired effects in several other regions that we cannot separate out.
opiates are a pretty good example. they have powerful pain-relieving properties when they bind opioid receptors in the ascending and descending pain pathways. they also have powerful reinforcing properties when they bind opioid receptors in the ventral tegmental area and nucleus accumbens, and depress respiration when they bind opioid receptors in the brainstem. (i’m being general in this post, if you want more details on opiates i have a better explanation here.)
so in short, if you’re looking for a certain effect due to drug action in a certain brain region, we’re stuck with all the other effects from all the other brain regions, too. this is why it’s very hard to come up with effective CNS-active therapeutics with acceptable side effect profiles!
january- a new year’s gift!
ahh, my new year’s wish come true. the replacement for our old and dead, critical piece of lab equipment has arrived, and it won’t be long until i’m back to my ridiculous level of work efficiency.
february- now the only way out is through
oh man, i don’t know what i’ve gotten myself into recently. i bit off far more than i could chew last week. and again this week.
march- ancient history
a recent post at dr isis’ place had me wondering about my long-neglected private personal journal.
april- while i’m slammed with lab work…
leigh is super sleep deprived, highly caffeinated, generally exhausted, and cranking out some seriously fucking awesome shit in the lab.
there’s an interesting article in the news about paid sick leave and the swine flu thing
june- confiding
can we talk about nonacademic personal lives for just a brief second?
july-…
really… i’ve got nothing. no personal reflections, no thoughts on the hellish writing/defending process, no thoughts on the job search.
august- on role modeling
i don’t suppose being a child from an impoverished family makes you at all likely to have a family friend who is a scientist at a high-octane university far away doing some way awesome shit.
bonus august post- for those who are wondering
yes, today was the day.
[woot, escape from grad school! i was too zoned/exhausted/hyped/other conflicting things to post much.]
september-yes, i am alive
i’m still here, getting life in order.
october- re-evaluation
i was pretty fucking pissed off the other day.
november-omg! dental insurance!
i haven’t had that in YEARS! i’m so excited that it’s even an option!
december- this post.
it’s been a wild year, folks. crushing pressure, followed by the end of grad school, a change of scenery, and a new job (well, new everything really). i thank my readers- the lurkers and the commenters- for riding through it with me.
for more than ten years i’ve been venturing through this life, masquerading as an independent adult. climbing a steep mountain of learning how to actually be an adult, how to interact with other adults, realizing my vision of success, multiple adolescent detours into major failure, finding appropriate role models, managing my life, my relationships, myself.
wandering through the paths that i’ve taken has taught me a lot of things. about how the world isn’t fair. and how the hand you’re dealt is nothing more than the hand you’re dealt. not luck, not fortune, not fate, not destiny. some of us come from nothing and scratch and claw our way up. some of us come from everything and struggle to find our way in the world. and every possible thing in between. that’s the way shit is. speaking from the former perspective, i can tell you how unfair my life has felt. as a child i used to ask myself, how come i didn’t get the two-parent family and the comfortable home in the suburbs, the warm jacket when it was cold and anything more than the food stamps would buy us? surely i would have been happy and successful with that kind of life backing me up. back then, i didn’t get it. i thought the world was harsh and cold, but for the wrong reasons.
i will say that coming here by way of the path i’ve taken has its distinct advantages (among the multitude of disadvantages i’ve had to fight through). i’ve got true grit, some serious life experience, and i’ve learned how to get what i want. i’m still working on the confidence, but i can project it like a pro. when i want to, i can crank up the intimidation.
the major con being the anxiety/memory disorder running rampant…
i also learned that just because one part of your life is tough, it does not grant you reprieve elsewhere. nothing evens out. you break through one barrier, and things fall apart somewhere else. you repair that mess, and before you can sit down and take a breath, something else happens. you keep busting your ass in hopes that at some point, you will have worked “hard enough” to earn the life you want. but nobody tells you what’s enough to meet that nonexistent goal line where everything becomes wonderful and effortless and happy. you learn the hard way that you define your “enough” and it sets a lot of things in your life accordingly.
it’s not simple. the ideal here in america is that hard work is some kind of virtue. good people work hard every day of their lives and are consistently rewarded for it. lazy people are bad people and should not get rewarded for anything. that is total fucking bullshit which is not based in reality but in false morals. as are most idealized visions of anything.
i’ve learned that i need to break away from this idealized bullshit and see the world for what it is. busting my ass every day with no rewards does not lead to happiness. it just makes me feel like i’m wasting my life by not having a life. because ya know what, i don’t live to work. i have had very few good role models in my life, but the good ones have really been great. one of the very important things i’ve been told, by one of the hardest working people i know, is that you need to protect your time. and that’s something i’m just now learning to do.
i’ve lived through pain and suffering that seems impossible through the eyes of my present self, but i’ve experienced such tremendous joys too. the joys don’t yet exceed the pain, and i have spent a lot of time and effort in pain avoidance maneuvers. i’m not owed joys simply because of what i’ve been through. it would be nice, and i’m going to chase them down as hard as i can.
we’re all just making this shit up as we go, i don’t believe for a minute that any of us really know what we’re doing. and life is too hard, too short, and has too much potential for pain for me to spend my time chasing after anything other than what makes me happy.
so fuck you, world. i’m just doing what i have to do here, and i’m chasing hard after that job i want in that big beautiful city. i’m going to spend more time with the siblings i don’t know well enough, and goddamnit i’m going to stay somewhere for a while and have a family. i have dreams, world. for a girl who once didn’t believe she would see the age of 18, and lived accordingly… in this new life of mine, i can see the sadness and desperation on display in that past life. and i am getting tired of waiting and wanting to truly live something better.
dear general world of mentors:
ok, we are all human. we all presumably have some sort of life outside the workplace that contributes to who we are as a person, and i appreciate that small shared personal connections can enrich a professional connection. in fact, i have found a lot of enjoyment in some of these little personal connections.
i’ll admit it, i’ve even received valuable advice for personal things that i have shared in some of the longer-lasting and more trusting working relationships. (though reaching that level took a while.) and when i’m through working for you, yes, i can consider you a friend of sorts for the personal interactions we had along with the professional ones.
but there are many, many, MANY things i do not want to know about you. because you are my boss. because i do view you as a professional first. and i am here to learn how to be a professional, through your influence.
so look. in general, we’re pretty cool as it stands, alright? for instance, i’ve really appreciated the professional-development stories that put me a little more at ease about my own professional development. i get it, you used to be one of the gang in the lab, not the boss-person. and maybe it’s strange, being on the other side of that balance. but there is a line, and it gets kinda fucking weird from this perspective when that line is crossed. until we’ve had a little more time to establish the professional relationship and i’ve had some more time to figure you out, let’s keep just a little farther away from that line. then we can look back and laugh about it later.
kthx,
leigh
some of these memories are fuzzy. some are clear as day.
#1
high school junior leigh is into chemistry. she is also enrolled in a psychology class, where she occasionally makes an appearance. occasionally.
in one of the rare scenarios that leigh is present, the teacher mentions use of lithium to treat bipolar disorder.
lithium rings a bell in leigh’s not-particularly-focused mind. that’s chemistry. wtf? why would you give someone a metal to treat a mental disorder? she asks. (i think i even said “what the fuck” but that’s another story.) the teacher has no idea. seizing the opportunity to maybe connect with leigh in some way other than not checking her name on the attendance reports, she encourages me to find out. who does leigh ask? her chemistry teacher. ha.
unless i’m forgetting something, which i admit is highly likely, this was leigh’s first neuropharmacology discussion. little did this delinquent know what she was getting her ass into.
#2
the phone rings. i’m at my desk working on graduate school applications. the fixer answers the phone. footsteps on the stairs, coming to get me.
“it’s for you.” the fixer looks bewildered.
alright… who could this be?
“hello?”
“hi…,” says a nervous voice on the other end of the line.
“i… um… my name is [firstname lastname]“
wait a minute. isn’t lastname my biological father’s name? i… oh fuck.
“…and my dad is, um, your dad. well, i mean your biological father.”
oh fuck, really? really? this is the first time in my life that i’ve randomly thought i need a fucking cigarette, and i don’t smoke.
“my… well, our… grandparents in [small city near hometown] saw your and the fixer’s engagement announcement in the paper. they sent it to my… our… dad. we all sat down and read it… we think you look like [middle sibling].”
jeezus tapdancing christ! i look like someone? they actually think about me? what the fuck is going on here? what do i even say? am i capable of speech right now? … ah, the answer to that is a resounding no. um. maybe she’ll keep talking until i get over this shock.
“i thought i would try to contact you. i saw in your announcement you’re going to [small state u]. i’m at [state u, another campus]. so i looked you up on the student system. and… well… congratulations! and hi.”
i gather myself
we had a nice conversation, my new sister and me. that opened the door to the other half of the family i knew i had but never… had.
#3
college sophomore bio prof stands in front of the class and announces, “my name is [firstname]. don’t you dare call me doctor [lastname]. i was a mediocre undergraduate. i got a lot of Cs. i am living proof that anyone who wants it badly enough can be a phd”
first time the idea entered my mind… “ya know, if these guys can do it, why can’t i? bah, who am i kidding? but… hmm”
famous last words, i say.
it’s funny how different my life has become over the last several years. it all started in grad school. the work-takeover-of-life took a sharp curve upward. not immediately, but years 2-4 were the exponential growth phase, and they weren’t fun. most of year 5 and the postdoc transition was, i think, simply a vertical line. all work all the time. no life.
well, i feel like after a few months on the job i’ve gotten my feet under me a little bit. some things are feeling much better, some things that irritate me remain unchanged. i’m back to feeling like i have some bastion of control over my work universe. and i think i’m being a pretty damn good postdoc for my level of experience, considering the circumstances. i am meeting my own expectations, which i try to set higher than those i receive from the rest of the world. work is finally hitting a plateau, but the rest of my life is on a crash course.
the problem is that i am not applying this careful construction to the rest of my life. see, my stress/anxiety-related problem is really kicking the living shit out of me lately. it’s been heavy stress for months- MONTHS- and i think i ran out of fuel sometime in the middle of moving to postdoc city. some major but unbloggable shit. it hit me very hard when i was quite possibly at my weakest. at that point, i was already relying on alcohol and/or drugs to sleep… usually “and”. well, that pushed me off a cliff. since then, i’ve been scraping along trying to get myself off the ground again.
i’m told by an objective party that the circumstances are totally unfair to me, and i deserve to be upset about being totally and utterly fucked over. that nobody should have to do this. but i have little choice in the matter. unless i do something i don’t ever want to do.
but i’m awesome at putting out this air of having all my shit together. yeah, i’ve got it covered alright. covered up. what i don’t tell myself at work is that i’m also reading these papers to find out what is wrong with me. what i don’t share with the world is how i can’t sleep no matter how hard i try. what i tell the fixer is not to tell me is how many times i woke up in a cold sweat, heart pounding, hyperventilating. not to remind me of things he knows but i might not remember at the time. i ask him to forgive me, because despite having come to the conclusion that i should, i can’t afford to see a doctor right now.
i ask him to not blame himself for being unable to find a job, which is in part the reason i can’t afford that… because it’s my fault for bringing us here.
all this aside, i refuse to fail and am well aware that somehow i always manage to come out on top. i have the instincts to pull this off- survival instincts well-honed over many years of really relying on them. i trust in myself to do what needs to be done. but i’m wondering how much farther this can go before i do fail in a big way. i got a lot of failure out of the way during my early years of independence. it’s been a while since i’ve truly, royally fucked some of my own shit up beyond recognition. after all these years of keeping things on the straight track, i don’t want to watch it all come tumbling down around me.
i’ve been too functional, worked too hard, for too long to blow it now. i’m a little afraid.
and reality is fixing to get sucker-punched right back, because leigh doesn’t take kindly to such affronts.
after…
sixteen years i barely survived.
then two years of scraping by on nothing, home being where i made it, before reaching the age of majority.
three years of college, self-supported (with the gracious help of the fixer).
and finally five heavily punishing years of graduate school, the last two of which i returned the gracious help of the fixer by putting him through college too.
…all this followed by finding a suitable job in the worst job market of my life and a pretty ugly funding climate as well.
here i stand, on the top of that mountain of accomplishments. i did it! twenty-six years spent in total- the ones i remember spent telling myself i just had to make it through to [next step] and man, things were gonna be alright. though i looked before i lept every time, i kept on adding steps. racking up shit to do.
but you know what? things aren’t magically alright just because i crossed all those finish lines. i was telling myself this to get through all the challenges i faced. but i’m not home free just because i did all this shit. the accomplishments mean nothing if i don’t chase down the underlying reason for all these accomplishments. i didn’t do them just to do them. i did them so that my life would be better somehow.
the problem? all these things i’ve done haven’t given me the chance to figure out what that life is like, the theoretical and nonspecifically defined “better” one i’ve been chasing down. i can’t keep being this high-performance achievement machine, neglecting myself and things that are important. i realize i have no idea what this life looks like, where it is, or how to get there.
to some extent, we all are just making shit up as we go along. i get that. but the only example i had is a strict what not to do. so um… where do we go from here?
i’m really not feeling ready to start writing heavy stuff again after the dissertation and the giganto-manuscript. i feel like i pulled a writing muscle and need more time for it to heal or something. i don’t know.
grad mentor admonished me when i said i was tired of writing. said this is my job now! my reaction was something along the lines of, “oh, fuck.”
i’m pretty relieved that gigantoscript has not returned with an outright rejection yet… presumably, they’ve decided to review it. that means it’s off my back for a little while.
but now? it’s time to write some more. another grant application. and this is applicable to the blog too, i’ve really let this thing go in terms of pharmacology content.
generally, i have a hard time sharing bad things. i prefer to share the good stuff, and let the bad stuff just kind of hide away in the back of my life. but let’s break through the silence today. i don’t have much to go on, but i’m going to post something. even if it’s a random smattering of stuff.
-i’ve had some kind of really obnoxious illness for about 5 days. i’m very tired. at least it is limited to my sinus passages.
-the fixer quit smoking yesterday- cold turkey- due to lack of funds. he is extremely unhappy.
-net result is a very quiet home today. me sinking into my illness-induced misery and some less than exciting data analysis, and him keeping to himself because he’s in a very foul mood.
-i went to a seminar last week that ended up being a false front for some weird ass program recruitment thing for postdocs. not thrilled, but thanks for the free lunch i guess.
-considering what to do about the growing-term spousal unemployment. i caught a job ad that was practically made for my desired career track and to-date training in a bigger city. i’m going to apply and see what happens- once i’m more clear-headed. right now i’m not with it enough to sell myself.
-regardless, when my contract here ends, if the fixer is not using his college degree, then we’re moving to Semi-nearby Big City.
-i’ve been awake for about 4 hours. i kinda want to take a nap now. yeah, i’ll go do that.
interesting how everywhere you go, there’s that one person. you know who i’m talking about. the one who’s trying to make themselves look good, by trying to make everyone around them look bad.
you’d think the most direct way to make yourself look good is to accomplish shit, and kick ass, create a collegial environment, and that kind of thing. internal standards. the kind of actions that earn you the respect of those around you. right?
but not that one person. that one person is so externally focused, that their own work begins to suffer. as their work suffers, they need to swing more vicious attacks at others to continue making themselves “look better” – which, as everyone sees their game, eventually quits happening. because nobody bothers to waste their time talking to that one person anymore.
these types will assuredly destroy themselves on their own. no intervention is required from you except staying the fuck away from them and avoiding any destructive radius around them. it requires a little patience, but is uniquely satisfying to watch their own douchebaggery take them down in flames.
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