Science Fiction and Science Fact

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Brooke picked up “The Immortal Life of Henrietta Lacks” in e-format from the library a few weeks ago, and as it’s a book I’d heard of and had some interest in, I joined her in reading it. Overall, it was a fascinating tale of how a black woman named Henrietta Lacks in the American South of the early-1950s died of cervical cancer, but samples of her cancerous cells survived in a dish (now known as HeLa cells), paving the way for not only the modern technique of cell culture, but also the discoveries that would develop the polio vaccine, new cancer treatments, and unlock many secrets of genetics.

While the book covers the science in a comprehensive, yet very readable manner, it also tells the reader of what happened to Henrietta’s family in the aftermath of her death, and the fact that they not only had no knowledge of the fact that Henrietta’s cells were being used in research, but they also received no compensation whatsoever for the discoveries that came from it.  When the family eventually discovered what had been happening with HeLa cells over the previous 20 years (seriously…20 years after her death, the family found out…), they didn’t understand what was going on, partially because researchers didn’t take the time to explain it to them, but also because many of them never completed high school, let alone took a single biology class.

This passage jumped out at me:

Deborah realized these movies were fiction, but for her the line between sci-fi and reality had blurred years earlier, when her father got that first call saying Henrietta’s cells were still alive.  Deborah knew her mother’s cells had grown like the Blob until there were so many of them they could wrap around the Earth several times.  It sounded crazy, but it was true.

“You just never know,” Deborah said, fishing two more articles from the pile and handing them to me.  One was called HUMAN, PLANT CELLS FUSED: WALKING CARROTS NEXT?  The other was MAN-ANIMAL CELLS BRED IN LAB.  Both were about her mother’s cells, and neither was science fiction.

“I don’t know what they did,” Deborah said, “but it all sound like ‘Jurassic Park’ to me.”

This conversation took place in the early-2000s, though Deborah, Henrietta’s youngest daughter, had been reading articles like the ones mentioned for decades, especially in the early years before the media and society really could grasp the power and utility of cell culture.  Sure, researchers were making “hybrids,” but what exactly did that mean?  The articles were sensationalistic, rarely providing enough background information to explain the meaning behind what researchers were doing (i.e. not making “man-animals”…).

But a lot of it goes back to the lack of education.  The Lacks family simply could not understand what was happening with Henrietta’s cells because they barely had a concept of what a ‘cell’ was, let along the technologies and diseases HeLa cells could (or did) help cure.  Heck, I remember trying to explain my graduate work to my 90+ year old grandmother (who possibly never took a biology class, and even if she did, it was in the early-1930s…), and that was extremely difficult.  It’s not that she wasn’t intelligent: she just didn’t have the background knowledge to understand much of what I was telling her.

As scientists, I think many of us expect that society, as a whole, has a basic understanding of how the world around them functions, but I have to wonder if society understands less than we think.  We expect that people over the age of 50 have taken a biology class before, but forget that biology has come a long way since they took those classes in the 1970s (when cell culture was still in its infancy).  We further don’t recognize that many of our aging population (i.e. people older than 60) haven’t had a biology class since the 1960s or earlier, if they took a ‘biology class’ at all.  And these are the people that we’re marketing countless drugs to during the commercial breaks from the evening news.

We need to get better at recognizing that “science” moves faster than society’s understanding of it. Perhaps this is why researchers have a tough time getting the concepts of “global climate change,” “evolution” and “childhood vaccination” across to certain segments of the population.  If they had the scientific background (or the will to learn more on the subject from primary literature, rather than silly blogs like this one), perhaps our society could move forward on many fronts, whether environmental, sociological or spiritual.

Though it’s important for scientists to communicate more effectively, it’s also incumbent upon society to start listening.  Otherwise, we are all doomed to repeat the failures presented in the book.  It’s definitely worth a read.

Neuroscience 2012

A shot from inside the conference hall, looking toward the poster boards.

Yeah, yeah, I know this happened almost a month ago now, but I’ve been meaning to post something about my trip to New Orleans and just haven’t had a ton of spare time to get it done.  Better late than never, eh?

It’s been almost three years since I last attended the annual Society for Neuroscience meeting.  On previous occasions, I’d gone to San Diego (2007), Washington, D.C. (2008), and then my last one in Chicago (2009).  Ever since starting grad school at SLU, I’d heard stories about “the last one in New Orleans” (that will go undescribed here…), but unfortunately, due to Hurricane Katrina, the SfN meeting couldn’t return on schedule.

That is, until 2012, when, coincidentally, I had my next chance to go.

Taking a step back, the reason why this conference is held in a few specific cities is that there are only a few specific cities capable of hosting about 28,500 conference attendees.  New Orleans was one such city, and taking it out of the rotation meant that Chicago had to be substituted, as it had a conference center large enough, and also enough hotels within a reasonable distance to hold all those people.  Unfortunately, Chicago’s conference center just isn’t in a very good location and its overall configuration isn’t ideal for this particular convention (the locations of stair cases, the number of floors, etc).  The logistics of handling 28,500 people can be handled much easier in New Orleans, San Diego, and D.C., at least so far as I’ve seen.

Regardless, I flew down on Friday, October 12th and returned on Wednesday, October 17th.  I presented a poster during the very first session, Saturday afternoon, and had a bit more traffic than I expected to have, as most attendees are arriving on Saturday and/or Sunday and could easily miss my poster.  Still, it was nice to get it out of the way early, freeing up additional time for the rest of the week.  Overall, I attended some good talks, wrote plenty of notes, and got a few ideas on new experiments to run.

Crescent City Blues and BBQ Festival

 Of course, this is New Orleans, after all, so the meeting wasn’t where all the fun was had.  I was splitting time between lab members from here at Wash U, and others from SLU.  Mostly, that split depended on what time of the evening it was: if it was early, it was the Wash U crowd, and if it was late, it was the SLU crowd.  One important exception was Friday night, after watching the Cardinals win Game 5 of the Wild Card Series against the Washington Nationals, we stayed out a bit late.  That weekend, there was a BBQ & Blues Festival going on, so we stopped by for some good food and tunes on Friday and Saturday evening for dinner.  They had it set up with a series of tents hosting a variety of different wares, and then a live stage with different musicians taking their turns.

I should remind you that Brooke and I took a trip to New Orleans in 2005, just after we got married and before Katrina rolled through, so I had already done much of the “touristy” things you’re supposed to do on a visit to the area.  This time was more focused on the food and night life (and science, of course… :-)).   I still stopped by Central Grocery for a muffuletta, had some Pasta Jambalaya at Crescent City Brewhouse, and had Po’ Boys from a few different vendors.  Needless to say, the food was spectacular.

I tried an oyster, though.  That was, perhaps, the absolute worst thing I have ever ingested.  Never.  Again.

Bourbon Street...er...late at night...

Again, last time around, Brooke was still falling asleep around 9:00 pm (well, she still does, to a degree, but she can stay up later now than she used to…), so we didn’t really stay out late.  This time, however, I was hanging out with night owls, so we hit up a variety of different establishments up and down Bourbon Street and, believe you me, I was genuinely surprised at the number of people out at 2:00 am on a Sunday night in mid-October.  I can’t imagine what it would be like during Mardi Gras.  The number of folks we saw in Soulard for a single day for Mardi Gras in February was probably approaching what I was seeing on a given weekend in October in New Orleans, and I don’t think the number of people was directly related to the number of geeky scientists that also happened to be in town.

Regardless, I had a really fun time down in New Orleans.  The city seemed a bit nicer than it was in 2005, the populace seemed genuinely happy to have us all there (28,500 people bring in a lot of sales tax revenue), and I think the conference, as a whole, was glad to go someplace warm, instead of Chicago.  It was great to hang out with good friends in a different setting, learn some new stuff at a large science conference, and “get away for awhile” (though, Brooke did a good job potty training Meg in my absence!!).  I hope I get the opportunity to go back sometime!

Empiricism vs Rationalism

As part of the grant I’m on at work, I am expected to attend “continuing ethics training” each year.  Last Wednesday was the first of two sessions, each a little over an hour long, and I ended up presenting a case study to the other folks in the room regarding the way science is conducted and how it is perceived by the general public.  This past Wednesday, however, we had a guest speaker in the form of Stephen Lefrak, a pulmonary physician that also has research interests in medical ethics.

He covered a range of subjects, but he specifically highlighted a series of studies he was involved with over 10 years ago, studies published in the New England Journal of Medicine, among other high profile journals.  Studies funded by the NIH and carried out by the National Emphysema Treatment Trial Research Group (NETT).  These studies involved a surgical procedure for patients with emphysema, where portions of the lung with damaged tissue would be removed, and the rest of the lung (presumably healthy tissue) would be restructured to form a better-functioning respiratory organ.  Lefrak and his colleague here at Wash U were involved early on with the trial, but left after they had serious ethical concerns, one of which centered on the idea of a “randomized controlled trial (RCT).”

For the sake of simplicity, an RCT is essentially the idea that you apply one of two (or more) potential treatments to a given individual, and that individual is selected at random from a given group.  In this case, the treatment was the surgical removal of lung tissue (presumably damaged) in order to refashion a healthier lung, and the group was emphysema patients.  However, and importantly, it was known at the time that you can’t just do this to someone that has lung damage spread throughout the lung: it only works if there is healthy tissue still in there to salvage.

Lefrak knew it wouldn’t work if the trials were carried out at random (i.e. paying no attention to the quality of the patients lungs, or whether they had healthy lung tissue remaining, or whether they had a “homogeneous” mix of damaged and undamaged tissue).  However, when this concern was raised in the pages of NEJM, he was essentially told that he couldn’t “know” it because an RCT had not been done to prove it.

As a result, almost 50% of the patients it was tried on ended up dying, for the very reason Lefrak and colleagues warned them about.

Which brings us to the title of this post: empiricism vs rationalism.  “Empiricism” is what drives the belief that an RCT is essential to making the claim that this kind of lung surgery is “dangerous” to a subset of individuals.  “Rationalism” is behind the idea that we actually know things about how the body works and can make an informed inference as to what the outcome would be without having to do the RCT to “prove” it.

The example Lefrak gave is that an RCT to prove that you need a parachute to jump out of a plane would be silly.  We already know the answer.

As Lefrak talked about his experience, it got me thinking about where our knowledge comes from and how we build upon it.  Whether I concern myself, personally, with “evidence” more than I should, without thinking rationally about a particular subject in order to come to a conclusion.  I’d consider myself to be a “rational” person, but perhaps not.  Then again, as he described what the surgery was seeking to do, my physiology training assured me that I would have been on his side from the beginning, rather than advocating the continuation of the NETT work.

It’s just something we, as scientists, ought to consider more often than we typically do, I guess.

Primer: Electrophysiology

These posts, tagged “Primer,” are posted for two reasons: 1). to help me get better at teaching non-scientists about science-related topics; and 2). to help non-scientists learn more about things they otherwise would not.  So, while I realize most people won’t read these, I’m going to write them anyway, partially for my own benefit, but mostly for yours.

It’s been awhile since I posted one of these, but as I’m working on radically different science than I have in years past, and people ask me “what I do,” I figured I should take the time to explain, to some degree.

Wikipedia defines “electrophysiology” in the following way:

Electrophysiology (from Greek ἥλεκτρον, ēlektron, “amber” [see the etymology of “electron”]; φύσις, physis, “nature, origin”; and -λογία, -logia) is the study of the electrical properties of biological cells and tissues. It involves measurements of voltage change or electric current on a wide variety of scales from single ion channel proteins to whole organs like the heart. In neuroscience, it includes measurements of the electrical activity of neurons, and particularly action potential activity.

So, in the most general sense, I’m “listening to neurons talk to each other,” and occasionally, “interrupting their ‘conversations'” in various ways.  When I talk about “conversations,” I’m referring to the act of neurotransmission, whereby one neuron sends a chemical signal across a synapse to another neuron, resulting in the propagation of that signal (an action potential), or sometimes the inhibition of another signal.

As I talked about in a previous primer, in order for an action potential to occur, various ion channels in the membrane of a neuron must open, allowing sodium (Na+) from outside the cell to come in, and potassium (K+) to go out.  Other ions will play roles as well, including chloride (Cl-) and calcium (Ca2+).

Using electrophysiology, it is possible to measure the movement of these ions across a cell membrane using relatively simple principles of physics.  Specifically, [V=IR], or [voltage = current X resistance].  If you hold two of the terms of this equation constant, it is possible to determine the third term.  Effectively, we do this using a “patch pipette,” a small, sharp, glass tube that has a wire electrode running through it.  If you know the resistance of the pipette, and you hold the electrode at a constant voltage, you can measure the current across the membrane of a cell (i.e. the flow of ions).

In short, this diagram describes the actual process of making this measurement, using a technique called “patch clamp“:

Looking through a microscope (like the one pictured above), you move one of these glass electrode pipettes to be just touching the membrane of a cell.  You have to be very careful so you don’t puncture the cell, thus damaging the cell membrane to the point where you can’t make accurate measurements.  You then apply a small amount of suction using a syringe to actually suck some of the cell membrane inside the pipette.  Once you have a strong seal formed (typically termed a “gigaseal”), you can apply a brief, large amount of suction with your syringe to rupture the membrane of the cell, where now, the inside of the cell is being exchanged with whatever you put on the inside of the pipette.  The internal solution of a pipette is usually something like potassium, basically trying to recreate what the inside of a cell would be, aside from all the organelles, however you can add compounds or drugs to manipulate the actions of channels you are trying to study.  Typically, though, you apply drugs to the outside of the cell, as well.

So, a real-world example of how this technique is used would be in my study of NMDA channels.  The NMDA receptor is a sodium channel and is very important in neurotransmission, but especially in memory.  When I have a cell “patched” like in the diagram above, I can apply the drug, NMDA, to the cell and see a large sodium current on my computer screen, kinda like this one.

So, over time, when a drug like NMDA or this “Blocker” is applied, you can see a change in the current (measured in “picoamps”) across the membrane of the cell.  In this case, we would read these data such that NMDA opens its channel and sodium ions flood inward, then that current is reduced by the “Blocker” that was applied for a few seconds, and then once the application of the “Blocker” was stopped and NMDA alone was applied to the cell, the inward sodium current increased again.

These traces allow you to get information about how channels are opening, what ions are flowing in what direction, and to what degree drugs like this “Blocker” are affecting channels.  It is work like this, for example, that led to characterization of benzodiazepines and barbiturates, drugs that interact with the GABA receptor, a chloride channel.  Without these techniques, it is difficult to know how a drug is affecting a channel at the cellular level.  Just about every cell in your body has channels of some kind, as they are very important for maintaining the function of that cell.  Neurons are just highly specialized to require ions more than some other cells do, though heart cells are also studied in this way, among others.

Effectively, these techniques allow you to determine how a cell works.

Fred Flintstone Wants To Kill You

I’m slowly catching up on podcasts from the last few weeks when I wasn’t really in Podcast Listening Mode, and recently, I listened to On Point’s discussion on recent research on vitamins.  Much of the discussion focused on recent reports suggesting that over-dosing on vitamins for years could do more harm than good.  Specifically, they discussed a recent study called the Selenium and Vitamin E Cancer Prevention Trial (SELECT) where men took the daily recommended dose of Vitamin E and were found to be 17% more likely to develop prostate cancer over the 7 years they were followed.  This news comes after another recent study from the Archives of Internal Medicine suggesting that multivitamins, folic acid, and iron and copper supplements may increase mortality in older women.

This all reminds me of what Dr. Shaffer told us in psychopharmacology class back at Truman: you don’t need vitamins if you eat a healthy diet.  Human physiology is set up to absorb the nutrients you need and get rid of the ones you don’t, provided you eat the diet your body needs to survive.  This includes vegetable, dairy, grain and meat sources.  If you start removing any of those sources of food, you either a). replace those nutrients with something like a multivitamin, or b). die sooner.  Apparently, however, new data like those referred to above suggest that even with the replacement of nutrients, your body still may not be very happy with you.

Brooke and I talked about this a few days ago and we both had a question about Folic Acid (Vitamin B9) intake, as this is one of those vitamins pregnant women are instructed to take to limit the risk of congenital malformations of children, including spina bifida and cleft palate.  The recommended daily allotment of Folic Acid is between 400 and 800 ug for a pregnant woman per day, though your doctor may prescribe more if there’s a history of problems in your family.  Bear in mind, however, that it’s important that women of child-bearing years have Folic Acid in their diet or take supplements before they are pregnant, as it’s more important in the early stages, before many women even know they’re pregnant.

Speaking of which, what are the ways to get Folic Acid in your diet, aside from a pill?  Spinach, peas, beans, egg yolks, sunflower seeds, white rice, fortified grain products (e.g. pastas, cereals), livers and kidneys, among others.  Now, I ask you: How many women between the ages of 18-25 are eating anything from that list on a daily basis?  I’d guess not very many.  They’re probably going to get most of it from breads and cereals, though the recommended daily allotment of folate is added to the product: it’s not endemic to wheat.

(Side-note: The U.S. government, on their Women’s Health fact sheet, says that vitamins are still essential to ensure you are getting the daily allotment of folate every day, and that it’s possible to do so by diet alone, yet difficult.  Anyone reading this should go by what their doctor tells them.  I’m only using folic acid as an example.  I am, by no means, a medical professional.  :-))

I guess my larger point is that vitamins are alright, but trying to rely on them in order to avoid eating foods that we as Homo sapiens have evolved to require over millenia is unwise.  It’s more important that we get proper dietary sources of vitamins and minerals that our stomachs have “learned” to take advantage of for generations.  This isn’t to say you should only eat organic food, or only eat food that you grow yourself.  Sure, organic sources can be healthy, but I’d argue that it’s better you eat your broccoli every day regardless of whether it’s organic or not.  Women of child-bearing years should be eating food from the outlined sources above anyway.  Men at risk of prostate cancer should be eating grapes, leafy green vegetables, and avoid trans fats anyway.  Heck, regardless of whether you’re “at risk” of prostate cancer or “at risk” of becoming pregnant, these are things you should be eating anyway.

So yeah, I don’t really think that vitamins are that bad for you.  But what is bad for you is trying to rely on them, or other supplements, as a substitute for a healthy diet.

(Final Note: An actual medical professional posted this article up on Huffington Post to help assure people that they shouldn’t necessarily stop taking all their vitamins and that there are some flaws in the conclusions being drawn from these studies.  As with anything in science, more studies are needed to come to any real conclusions on this matter)

Back in the Swing of Things

Here's what I'm using all day now.

I’m sure I’ll have more to report on in the future, but for right now, I can safely say that I’m settling in at the new job.  I’ve been telling people for awhile now that there would be a definite “learning curve” with the science carried out here, and believe you me, I wasn’t kidding.  I’m having to re-learn basic circuit mechanics (i.e. resistance, capacitance, voltage, etc.) from physics class 8 years ago in order to comprehend the bulk of what I’m doing, so that’s where much of my learning is coming from.  The rest of it is coming from the actual manipulations of cells in order to collect meaningful data.

Basically, what I’m doing now in the lab of Steven Mennerick in the Department of Psychiatry at Washington University, is termed “electrophysiology.”  It’s a technique used to record changes in current and voltage across the membrane of a cell, in this case, hippocampal neurons from mice.  I’ll write more about this in a Primer sometime after I get more settled, but in short, the process involves attaching an electrode to the interior of a cell, and then a second electrode outside the cell in the surrounding fluid.  Depending on what drugs and ions you have present in the two locations (intracellular and extracellular), you can record peaks that look very much like ECG recordings from your heart.  These peaks will tell you whether sodium, potassium, calcium, chloride, etc. are entering or leaving the cell, which in turn tells you about how the cell functions.  Specifically, it gives you insight into neurotransmission, as the process of a cell receiving a neurotransmitter (e.g. dopamine, adrenaline, etc.) must involve some change in the flow of ions across the cell membrane.

The rig pictured above is the one I’m learning on.  It’s a large microscope with some tubes and electrodes running up to the state where the dish of cells sit.  Then, you use some little knobs and widgets to move the electrodes very slowly toward the cell so you don’t kill it by “popping” it.  So yeah, this takes some practice.  You have to make sure you don’t break the cell open, you have to make sure you don’t damage your electrode, and you also have to make sure you’re doing everything fast enough so that certain components of the system don’t “go bad” to the point where you need to replace them.  There’s a healthy balance between speed of operation and “care” of operation in all of this, for sure.

Aside from learning how to actually puncture and gather data from the cell, I’m having to learn about the aforementioned physics of circuits.  Good thing my Dad works with circuit breakers, just in case I ever need some help.

I’m definitely making progress, though.  I’ve been able to successfully puncture (or “patch,” as the technical lingo goes) more than a few cells, so right now, I’m working on consistency more than anything.  I’m hoping to get some more reading done today or tomorrow so I begin to understand why I’m doing some of the things I’m doing.

At the very least, it’s keeping me busy.  :-)

Primer: Psychopharmacology, Part I

These posts, tagged “Primer,” are posted for two reasons: 1). to help me get better at teaching non-scientists about science-related topics; and 2). to help non-scientists learn more about things they otherwise would not.  So, while I realize most people won’t read these, I’m going to write them anyway, partially for my own benefit, but mostly for yours.

It’s crazy to think that I’ve been posting these things monthly since last June.  For my first Primer, I talked about Pharmacology, as I had just completed a Ph.D. in it.  Now, a year later, I’ll elaborate further on the subject that got me interested in it in the first place: psychopharmacology.

As I wrote back then, I took a class at Truman State based out of the Psychology department that taught students about psychopharmacology, defined as:

Psychopharmacology — noun

the branch of pharmacology dealing with the psychological effects of drugs.

In broad strokes, we’re talking about how a drug can change your state of perception, whether it causes or alleviates hallucinations, alters your mood, dampens your emotions, and so on.  Something that changes your “normal psychological state” to something else, whether that be therapeutic or “recreational.”

In order to grasp what happens in your brain when your mood is changing, you need to have a basic idea of the structure of the brain and neurotransmission, both subjects I have discussed in the past.  For example, much of your cognition happens in the brain region called the Cerebral Cortex, and it is dependent upon neurotransmitters like acetylcholine and dopamine.  Alternatively, emotions like anger, aggression and fear tend to be centered in another region called the Amygdala.  Bear in mind that the varying areas of the brain “talk” to each other, and if you affect the signaling in one area, you may very well affect another area.  This may well be the point of any pharmacological intervention, but frequently, you get undesired consequences we call “side effects.”

Let’s look at the Cortex first.  Schizophrenia, a disease characterized by delusions, hallucinations and disorganized speech or hearing, is thought to be caused by misfiring neurons in the Cortex that release dopamine.  Therefore, if your cortical neurons are releasing too much dopamine, for any reason, you can end up with hallucinations and delusions, etc.  Interestingly, you can induce schizophrenic-like symptoms in an individual if you give them amphetamine or cocaine, both of which also increase the release of dopamine, though on a wider scale throughout the body.  For those with Schizophrenia, you typically prescribe an antipsychotic, a drug that inhibits dopamine release or reception.

The trick with drugs like antipsychotics, however, is that you want to inhibit dopamine release in the cortex, yet you want to limit that drug’s effect on other areas of the body where you still need dopamine release, or other neurotransmitters like norepinephrine that are responsible for completely different things (hence, side effects).  For example, if you were to design a drug to limit release of dopamine, you could fix their symptoms of Schizophrenia, but you could also affect mobility, as dopamine is responsible for voluntary control of movement.

This is how we arrived at “typical” and “atypical” antipsychotics.  The “typical” drugs were the first-generation antipsychotics that did a reasonable job at limiting schizophrenic symptoms, but also affected other dopaminergic neurons in your body (i.e. your movement).  People on these drugs for decades frequently came down with a movement disorder called Tardive Dyskinesia.  The second generation “atypical” antipsychotics were more specific to the Cortex, and limited schizophrenic symptoms while mostly leaving other dopaminergic signaling pathways alone, thus alleviating dyskinesias.

As another example, Depression is a mood disorder that makes you feel sadness, anxiety, and general hopelessness.  This disease is thought to involve the limbic regions of your brain, which includes the amygdala and the prefrontal cortex.  Depression, however, is opposite of Schizophrenia in that it represents a lack of the neurotransmitters serotonin and dopamine.  The drugs of choice used to be TCAs (tricyclic antipsychotics), a drug that blocked the reentry of serotonin and norepinephrine into neurons, thus prolonging the activity of these neurotransmitters.  In short, it made your serotonin work longer than it usually does, thus alleviating the need for production of more.  As with Schizophrenia, this earlier drug class generated a large number of side-effects because it affected norepinephrine and serotonin throughout the body.  Because TCAs worked on norepinephrine, that also meant that its action would increase in your body, for example, affecting your blood pressure through action on your blood vessels and causing arrhythmias due to action on the heart.  Once SSRIs were developed, they rapidly replaced the TCA drug class because they were more specific toward only serotonin and not norepinephrine.

Both Schizophrenia and Depression are examples of psychological disorders that can be treated effectively with some kind of pharmacological intervention.  Frequently, a given patient will end up trying multiple different drugs over the course of their treatment, and sometimes in various combinations.  Unfortunately, there isn’t a single “silver bullet” for taking care of a given psychological disease, as most people manifest the disorders in different ways, with different drugs being more effective at treating different symptoms.  While an SSRI may prove useful in the short-term, it’s possible a doctor will prescribe a TCA later on after the SSRIs lose their effectiveness.  Antipsychotics act similarly.  And more research is being done on new classes and new modifications to old drugs in order to make them more effective, and especially more selective toward their specific target(s).

The larger point to all of this is that the study of psychopharmacology is an effort to control one’s emotions and behaviors while not affecting the other aspects of their day-to-day life (i.e. side effects).  These drugs typically manipulate neurotransmission to some degree, and hopefully have some kind of selectivity toward specific aspects of a given disease rather than affecting all transmission of that particular compound.  This can be difficult, and can take decades to fully investigate, but it is certainly possible.  As researchers develop more complex maps of the brain, with more detailed pharmacological profiles, new drug classes can be produced that are more specific to a given individual’s needs.

As this is more than long enough, and I still have more to say on the subject, stay tuned until next month when I hit up Part II.

Primer: Cell Death

These posts, tagged “Primer,” are posted for two reasons: 1). to help me get better at teaching non-scientists about science-related topics; and 2). to help non-scientists learn more about things they otherwise would not.  So, while I realize most people won’t read these, I’m going to write them anyway, partially for my own benefit, but mostly for yours.

A good portion of my graduate work centered upon how a given cell will die when exposed to a specific toxin.  In order to develop therapies to prevent the death of that cell, the means by which a cell dies is important.  It’s also important how a cell doesn’t die, as I’ll explain later on.

We’ll keep this somewhat simple, though.  There are two (very) basic ways that cells will expire: necrosis and apoptosis.  Necrosis involves the destruction of the cell and, frequently, damage to surrounding cells.  Essentially, the cell ends up swelling and exploding, allowing the intracellular materials to leave and get into the surrounding tissue.  Frequently, necrosis is accompanied by extreme inflammation, causing things like white blood cells/macrophages, the cellular defenders against infections and invaders, to get to that area and try to clean it up.  In the process, they end up creating more damage.  Think of it like a “Scorched Earth” policy of eradication of a given problem.  “Take it out and everything around it to make sure we cleared it up.”

Apoptosis, on the other hand, is thought to be much more controlled.  It is a form of “programmed cell death,” meaning that there are mechanisms built into a cell to allow it to fail properly (unlike the United States banking industry…).  Effectively, when specific signals are received, the cell begins the process of dismantling itself, chewing up its own proteins, shutting down its processes, and packaging itself up for a clean removal by nearby macrophages.  Rather than the “Scorched Earth” means of cleanup, it’s more like putting things in trash bags and putting it out on the curb for the garbage truck to come by and pick them up for you.

Apoptosis is an extremely important process for other things, though.  In the early development of an organism, for example, the neural pathways of the brain and spinal cord are set up such that some neurons will make the proper connection and others won’t.  Those that make the proper connection with their target are strengthened, while those that don’t receive an apoptotic signal to shut themselves down and make way for other neurons.  Cancer, however, is an example of a disorder where the proper apoptotic signals are not received and the cell decides not to shut itself down as prescribed.  Instead, it can’t receive or interpret the signals and continue to reproduce themselves.  Eventually, it gets to the point where even the “Scorched Earth” means of eradication by inflammation doesn’t work.

So in general, your body would prefer to go the “apoptosis” route over the “necrosis” route, as the latter tends to produce quite a bit more damage to surrounding cells and tissues that your body would have to repair afterwards.  Once a cell has started down the path of necrosis, it’s difficult to turn back and save it.  Apoptosis, however, can be limited because it is so dependent upon intracellular signals.

This image is only a fraction of what’s actually going on in apoptosis, but does contain some of the basic signalling mechanisms.  Each of those little acronyms is a protein, coded for by a gene in your DNA.  Some of them are turned on because of a signal sent from outside the cell, while others are turned on when the cell starts doing something it shouldn’t, so it tells itself it needs to shut down and dismantle itself.  However, the key point is that there are ways to use inhibitors toward those proteins to slow down the death of cells, if not stop the death entirely.  Alternatively, in the case of cancer, some of those signals above aren’t functioning properly, and if you can determine which signal isn’t working, you can try to replace it, or “skip over” it and start the signal further down the line.  Think of it as a game of telephone where each of those acronymns above is a person, but “cancer” occurs when one of those people decides not to continue the game of telephone.  We could potentially use drugs to “skip over” that person and keep the game going, or to finish the analogy, to keep apoptosis going.

A lot of what I just said, however, is determined by the ability to personalize medicine.  There are a battery of tests that people are run through when they are diagnosed with cancer, but right now, only a few types of cancer can be targeted in such a way.  Usually, we just go the “Scorched Earth” route, much like your own body does, but instead we use radiation and chemotherapeutics.  Eventually, however, once drugs can be personalized to the individual (e.g. figuring out which person along the telephone line isn’t continuing on with the game), then we should be able to target that cancer specifically and shut it down.  Unfortunately, each person is different and each cancer is different (i.e. it isn’t the same person stopping the game in everyone’s situation: it’s sometimes someone else).  Each cancer has to be checked individually for which signal isn’t working, and that takes lots of time and lots of money.

But science and medicine is getting there.  Slowly, but surely.

What does “Rock Chalk” mean, anyway?

This past weekend marked my second scientific meeting since moving up to Iowa for my postdoctoral position.  The first one was last fall, when we hosted the Central States Society of Toxicology meeting here at the University of Iowa.  It didn’t really involve much more than a day’s-worth of work on my part, and was generally a decent time.  This weekend, however, was the first one when we actually went somewhere else.  And that place was Kansas.

We’ll go ahead and get this out of the way now.

I hate Kansas.

Moving right along…

It was the 2011 MIKI Meeting, a conference comprised of four midwestern Medicinal Chemistry programs from the University of Minnesota, University of Illinois at Chicago, University of Kansas, and University of Iowa (…hence, “MIKI”).  The meeting rotates between the four universities each year, and next year is Iowa’s turn again.  So it was very useful to see the meeting in action so we could start having some discussions over what needs to be done in preparation for next year’s meeting.

The general structure of the conference was similar-ish to others I’d attended in years past.  We left here by bus on Friday around noon to get down to Lawrence, KS in time for dinner and a mixer at a downtown location called Liberty Hall, where we had some buffet-style food, free beer (woooo!) and a “Trivia Night” competition between the different tables.  It was a good opportunity to interact with some folks from the other programs, which was kinda nice.  Saturday comprised the bulk of the meeting, involving 15 minute mini-talks from graduate students, a 1 hr keynote lecture, and then a 2 hour poster session, which I participated in.  That night, we went to another downtown locale called Van Go Mobile Arts for dinner, and then some of us went out again afterwards.  Sunday morning, we had some more 15 minute talks and then left on the bus by noon, getting back to Iowa City around 6:00ish.

In total, the weekend was pretty good.  This was a 200-person meeting, which is the optimal size, in my opinion.  In many ways, I liken it to a classic church youth trip (a la Youth Congress) where you are stuck in a van or on a bus for hours on end, then you get to where you’re going for the weekend and get placed into situations where you’re somewhat likely to interact with other people from other cities, as well as talk with people from your own group that you may not have interacted with in the past.  The meeting I normally go to, Society for Neuroscience, has more like 30,000 people attending, making it extremely difficult for you to interact with anyone but your own group.  In that respect, a 200 person meeting is much, much better for “networking,” and for learning more about your field and other people’s.

So despite the fact that we had to go to Kansas, the weekend was still pretty fun.  I got to meet some cool people from other places and interact with folks from here that I didn’t know all that well.  And Brooke and Meg survived for a few days without me, though it appears that Meg missed her Daddy to some extent (she did not like it when I left her at daycare today…).  Brooke said that they went to church yesterday and it seemed like Meg was looking for me, expecting me to be there.  Of course, she’ll be without her Daddy again next weekend when Brooke and Meg head down to the Lake for the annual “Girl’s Weekend” with Brooke’s family.

I’m sure Grandma will keep Meg entertained, though…  😉

Primer: Drug Discovery

These posts, tagged “Primer,” are posted for two reasons: 1). to help me get better at teaching non-scientists about science-related topics; and 2). to help non-scientists learn more about things they otherwise would not.  So, while I realize most people won’t read these, I’m going to write them anyway, partially for my own benefit, but mostly for yours.

There are a few ways to approach the general idea of drug discovery, but I’m going to try and tackle it from the historical treatment first, and maybe revisit it in a future Primer.  I am part of the Division of Medicinal and Natural Products Chemistry at the University of Iowa, and the two components of it, Medicinal Chemistry, and Natural Products, are both integral to the idea of developing new drugs.  Medicinal Chemistry is just as it sounds: the study of designing and synthesizing new drugs, using principles of chemistry, pharmacology and biology.  The idea of Natural Products, however, is a bit more interesting in that, just as it sounds, it studies chemical compounds “developed” in other organisms that may be useful as drugs.

The oldest records tend to cite the ancient Chinese, the Hindus and the Mayans as cultures that employed various products as medicinal agents.  Emperor Shen Nung, in 2735 BC, compiled what could be considered as the first pharmacopeia, including antimalarial drug ch’ang shang, and also ma huang, from which ephedrine was isolated.  Ipecacuanha root was used in Brazil for treatment of dysentery and diarrhea, as it contained emetine.  South American Indians chewed coca leaves (containing cocaine) and used mushrooms (containing tryptamine) as hallucinagens.  Many different examples of drug use in ancient, and more modern cultures, can be pointed to as early forerunners of today’s drug industry.

However, it was the 19th and 20th centuries that really kick-started the trend, as this is when modern chemical and biological techniques started to take hold.  It was in the 19th century when pharmacognosy, the science that deals with medicinal products of plant, animal, or mineral origin, was replaced by physiological chemistry.  Because of this shift, products like morphine, emetine, quinine, caffeine and colchicine were all isolated from the plants that produced them, allowing for much purer, and more effective, products to be produced.  Advances in organic chemistry at the time really helped with the isolation, so these discoveries wouldn’t have been possible previously.

In today’s world, there are a few ways you can go and discover a new drug:

  1. Random screening of plant compounds
  2. Selection of groups of organisms by Family or Genus (i.e. if you know one plant that makes a compound, look for more compounds in a related plant)
  3. Chemotaxonomic approach investigating secondary metabolites (i.e. Drug A functions in your body, then is metabolized in your liver to Drug B, which also happens to be functional)
  4. Collection of species selected by databases
  5. Selection by an ethnomedical approach

I think the latter two are the most interesting, especially with a historic perspective.  With the latter, we’re talking about going into cultures (a la the movie “Medicine Man“) and learning about the plants that they use to cure certain ailments, then getting samples of those plants and figuring out what makes them effective.  It has been estimated that of 122 drugs of this type used worldwide from 94 different species, 72% can be traced back to ethnic groups that used them for generations.

The discovery of new drugs of this type is actually somewhat worrisome as these cultures die out or become integrated into what we’d consider “modern society.”  These old “medicine men” and “shamans” die before imparting their knowledge to a new generation and these kinds of treatments are lost.

The collection of species and formation of databases is interesting, and only more useful in recent history due to the advent of computers that can actually store and access all the information.  With this process, we’re talking about going into a rain forest, for example, and collecting every plant and insect species you can find, then running various genetic and proteomic screens on the cells of each plant and insect to see whether they produce anything interesting or respond to anything.  This process can involve thousands of species across a single square mile in a rain forest, necessitating a great deal of storage space for the samples themselves, but also computing power to allow other researchers the ability to search for information on that given species.

An example of a “screen” that one could carry out would be to grow bacteria around your plant or insect samples.  If you ever heard the story of penicillin, you’ll know that Alexander Fleming (1928) noticed that his culture of Staphlococcus bacteria stopped growing around some bread mold that had found its way into the culture.  From that bread mold, penicillin, was developed as our first antibiotic.  The same kind of principle can be applied here: mix your samples together and “see what happens.”  If anything interesting happens, you then continue investigating that sample until you isolate the compound that is doing that interesting thing.

The isolation of that “interesting compound” can be very tricky, however.  In many cases, a particular anticancer agent or antibacterial agent may be housed inside the cells of our plant species.  Getting that compound out may be difficult, as it could be associated with the plant so tightly that you have to employ a variety of separation techniques.  And even after you apply those techniques, what you are left with may be nonfunctional, as the compound may require the action of that plant itself to work properly (i.e. the compound you want may still need other components to work).  Even after you isolate the compound you want, in order to make it a viable drug, you have to be able to synthesize it, or something like it, chemically in a lab setting.  Preferably, on a massive scale so you can sell it relatively cheaply as a drug to the masses.  These processes can be daunting and costly.

So basically, it can be fascinating to discover new drugs, especially ones that were actually “discovered” thousands of years ago by cultures that have long since died out.  However, you may find that “discovering” the drug may be the easy part – mass producing the drug could be the most challenging aspect of the ordeal.