“Whatever America hopes to bring to pass in the world must first come to pass in the heart of America.” –Dwight Eisenhower
I recently got my passport, and the above quote is inscribed on pages 7 and 8. I read it and immediately translated it to “Whatever the Ph.D. student hopes to bring to pass in the Ph.D. must first come to pass in the heart of the Ph.D student.” That interpretation may be stretching the bounds of my “artistic license”, but hey, it’s inspirational. The list of things I would like to bring to pass in my Ph.D. is fairly short; after “make a world-changing discovery”, “publish”, and “graduate” there isn’t much left and everything else listed is fairly optional. One additional thing that I would like to accomplish, as an aspiring teacher, is to learn to teach. Simple explanations can go a long way for a teacher; as Albert Einstein so famously put it, “if you can’t explain it simply, you don’t understand it well enough.” Of all the extravagantly complicated concepts in my area of research (pharmacology / tissue engineering), it seems that drug transport in the body is one of the most frequently misunderstood. It is such a bewildering topic that when attempting an explanation, I (and, I’m sure, other weary students before me) have often resorted to a dash of pixie dust, vigorous rubbing of gnarled hands and a quasi-confident declaration of “magic”, much to our scientific chagrin. In order to avoid such a miserable demise, and in an effort to take the illustrious Professor Einstein’s challenge to heart, I will attempt to clarify the vast, muddy waters of general drug delivery and transport via (yet another) analogy.
About a month ago, I travelled to Peru with a group of friends (hence, the passport). Throughout the host of fantastic adventures that our expeditions in the Central Andes provided, there were quite a few scattered setbacks and difficulties. One of the most noteworthy struggles we had in Peru (I’m sure the term “Struggle Bus” is more than applicable here), was attempting to secure motorized transport, in general. This was a significant difficulty for foreigners who spoke little Spanish, had never handled soles (“s/.” Peruvian currency) and were quite content to be led into strange vehicles by enthusiastic cabbies with slicked back hair. Few things will tingle your Spidey-senses more than being herded by a much-too-excited Peruvian cab-driver into a mid-90’s series Hyundai sporting 263,000 miles, a broken speedometer and a mismatching and (hopefully) unnecessary rear spoiler. One thing that will, though, is actually driving away in the aforementioned “vehicle” into the great unknown of downtown Lima, Peru. This is where our adventures in motorized transport, and, by virtue of simile, drug transport, began.
Many, many bodily processes are run by concentration gradients. When I think of concentration gradients I think of a dam on a river. The Limón Dam is located on the Huancabamba River in northwestern Peru, and, besides being useful for the purpose of storytelling, it is quite an impressive feat of engineering. A 12 mile tunnel was bored through a 6,000 foot mountain in the Andes simply to enable the dam to redirect water from the Amazon basin side of the Andes to the farmlands near the Pacific coast. And you thought shoveling your driveway this winter was tough. The dam itself holds back 44 million cubic meters of water – to put that in perspective, Minnesota’s own Lake Superior holds 2.1 billion cubic meters of water. This means that the Limón Dam is up against a measly 2% of the volume of Lake Superior, but let’s be honest, that’s still a lot of water. The weight of the water contained behind the dam forces some water out - literally presses it out with an enormous amount of energy that can be used to power generators. This is how concentration gradients work in the body - high ion concentrations (think calcium, potassium and sodium ions) either inside or outside of the cell push through to provide energy for “generators” that power further processes - DNA or protein synthesis, capturing and engulfing other proteins, removal of wastes, etc. For these things to happen there need to be enormous gradients and enormous amounts of ions, proteins, vitamins, etc. Cells are jammed full with connective proteins to retain structure, lipid rafts and protein complexes to traffic molecules and large cellular compartments to store raw materials or harbor specific reactions. Individual cells are like the rest of the body in that there is no empty space. So little free space, in fact, that it seems a miracle when anything is able to move through such a tightly meshed network of organic material. Which brings me back to our cab ride through Lima.
We had successfully loaded five large packs and five crazy Americans into our extremely compact Hyundai. Our driver seemed to have a disproportionate amount of space, but I guess he had to do this all day, liked being comfortable and probably never had a nickname like “the green giant” so who can blame him? The cabbie introduced himself as David and promptly whisked us out of our safe, cellular compartment of the “aeropeurto” and made a direct cut, diagonally, across three out of four lanes of a highway that moments ago seemed to be bumper to bumper. His maneuver, if done in the states, would most likely have generated a dozen well-deserved honks, several obscene gestures and a hearing at the county courthouse, but here, such illicit antics seemed to be expected if anyone was going to get anywhere. Everywhere I could look (which was limited due to my status of being squished and crushed by my friends and our bags), another driver was waving, cutting, tailgating, creating a new driving lane, and sliding between 18-wheeler flanked gaps that ominously threatened the next driver daring enough to test his luck and risk being crushed into the void. By some miracle of modern civilization, the entire gesturing, honking, engine-revving army of traffic moved forward. Aggressive cabs moved the mass forward, garbage trucks and busses slowed it down, but all in all, we moved.
Generally, drugs are delivered systemically. This means that if you or I were to take a medication (let’s use acetaminophen [Tylenol] as an example) it is first dissolved in the GI system, and promptly distributed to the vasculature where it is spread, very near equally, throughout the body. Tylenol is a small molecule, statistically insignificant in size compared to most proteins (imagine a single Tylenol molecule as a moped compared to a very large tour bus or semi-truck). This aids Tylenol mopeds in some cases, though, because they can, essentially, take the sidewalk or cut between traffic. Such small molecules have little trouble passing through channels, gates, pores and meshes that are naturally formed in the body to segregate and compartmentalize bodily functions. These molecules can get nearly everywhere, while large compounds (i.e., busses) often cannot.
The purpose of sending out our Tylenol mopeds is to cause a specific action. Imagine we were at the Lima airport, and we collected 1000 mopeds and drivers, told them to find all the coffee shops in Lima and released them into the highway headed for the downtown thoroughfare. Our Tylenol mopeds would have to move through the traffic packed highway, and into the city to cause their action. They each have a specific affinity - for our purposes, they have affinity for coffee shops and, when a moped reaches a coffee shop, it will park in front of it. Ideally, we would only have one moped in front of any given coffee shop (assuming we have at least 1000 coffee shops in Lima and drivers will keep going if a shop is already claimed by a moped). Most drugs act in this way also - their affinities allow them to bind to (or park on) only specific proteins or groups of proteins. When one drug is bound to a protein, typically that protein doesn’t want to accept binding of another drug.
As the Tylenol mopeds get released into the highway, we will lose some before they can enter any business district with an available coffee shop - they might run out of gas, get a flat, get in an accident, etc. Plus, they have to compete with other endogenous mopeds (not carrying Tylenol) that are fighting for space on the crowded highway, and in the streets, as well. This phenomenon, in pharmacology, is called “first-pass metabolism.” The GI system neutralizes some of the drug before it can ever reach its target. For some drugs, first pass metabolism significantly dampens its’ effect.
Once in the city, the remaining Tylenol mopeds search frantically for coffee shops. Unfortunately, some will get confused and end up parking in front of locations that are not coffee shops, simply because those locations serve coffee (i.e. restaurants). Mopeds that end up parked in front of the wrong locations represent what are termed “off-target effects.” These are, essentially, a drug causing an unintended signal or action in the body. Off-target effects are often responsible for the horrifying list of pathologic conditions required to be listed on every medication ever given a green light from our friends over at the FDA. Yes, it is possible that you will die from aseptic meningitis if you take Motrin. It’s also possible that you will be engulfed in a pit of quicksand tomorrow on your stroll into Plummer Building. You can’t win ‘em all.
If we were to increase the amount of Tylenol mopeds from 1000 to 10,000, we would encounter even greater problems. Releasing 10,000 mopeds out of the Lima airport could cause significant traffic problems due to excess broken down mopeds, blocked sidewalks and slowed traffic of other, already present mopeds. These problems could result in police being called to the scene to re-direct traffic or ticket our mopeds (immune response), or congested back roads and sidewalks (other off-target toxicity / side effects). Once in the city, we would flood the coffee shops of Lima with mopeds, potentially having 5-10 mopeds in front of each shop instead of one, and we would also increase our off-target effects by flooding los mercados y restaurantes de Lima. As I’m sure you can already guess, this situation represents an overdose.
To be fair, this offers an exceptionally simplified explanation of only a few concepts within an extraordinarily complicated topic. Drug transport, binding properties, mechanisms of action, and metabolism are determined by an expansive array of variables that encompass topics far beyond the scope of this short essay. Distilling these principles down to their most basic elements can be a useful tool for efficient communication, and can test the extent of our comprehension as well. Hopefully, this analogy helps clarify a few of the ideas thrown around in the pharmaceutics field, and will give some explanatory weapons to beleaguered scientists attempting an accurate description to the lay-person, while simultaneously resisting the urge to use their magic wands. Although, if you happen to have an extra magic wand lying around, I could use one. Some guy on a moped just drove off with mine.
Carl Gustafson is a second-year Ph.D. student in Michael J. Yaszemski's laboratory.