Tools for the Toolbox: The Pellet With The Poison

Here are all of the fictional poisonings I can name off the top of my head in a minute. (Okay, two minutes. Okay, three.)

The Court Jester (my childhood movie…you Disney kids got nuthin!)
Doctor Who (folds in Agatha Christie)
Hercules (aka: why you never see Hercules wearing a shirt anymore)
Gosford Park (If you haven’t seen it, you must! Excellent ensemble piece.)
James Bond (I’m thinking of the one in the poker game; I’m sure there are others too.)
Romeo and Juliet (with extra tragedy action!)
Rosencrantz and Guildenstern Are Dead (I’m cheating…didn’t want to do two Shakespeare plays in a row, so this is my way around it.)
Chuck (spies always like poison)
Wizard of Oz (I’m counting the poppies.)
Harry Potter (Basilisk!)
Lamentation (by Ken Scholes)
Batman (Batman!)
Socrates (okay, that’s historical, I know. But admit it, it’s fun having Batman and Socrates next to each other on a list.)

Okay, my *mumble* minutes are up. That’s a pretty wide-ranging list, isn’t it?

So poisons are everywhere in the stories we like to tell.

But what exactly is a poison?

It’s a thing you put into someone’s drink that makes them suddenly keel over at the dramatic turning point of your novel!

Well, yes…but why does it make people keel over?

Hint: it has to do with biochemistry.

NOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO!!!!!!!!!!!!!!!!!!!!!!!!!!!!

Hey, you survived the last biochemistry post!

?

Yes, exactly.

I’ll let David Tennant tell you how poisons work. (Note: I’m using the long version of this scene not because it’s medically plausible, but because Tennant and Catherine Tate have such a fun comedic dynamic.)

“Something’s inhibiting my enzymes,” says The Doctor.

Enzymes are proteins that are basically little molecular machines that make things happen faster in a molecular reaction. Biochemical processes are just strings of molecular reactions. So, enzymes are proteins that facilitate biochemical processes.

Uh…try that again, please?

Okay. Pretend you have Red Molecule and Blue Molecule, that fit into each other like puzzle pieces to make Purple Molecule. If they were left alone, they’d just bounce off each other in a very molecule-y way, and only rarely manage to bounce into the proper orientation where they click together to become Purple Molecule.

Enter Enzyme McAwesome.

Enzyme McAwesome is a protein that’s wrapped into a configuration that’s designed specifically to grab Red Molecule. When it grabs Red Molecule, the presence of Red Molecule makes the structure of Enzyme McAwesome change so that it now has a part that loves to grab Blue Molecule. When it grabs Blue Molecule, the presence of Blue Molecule changes the structure again so that Enzyme McAwesome slams Red Molecule and Blue Molecule together, in exactly the right orientation to make Purple Molecule. Then Enzyme McAwesome lets go of Purple Molecule, and is ready to grab another Red Molecule and start the process all over again.

If something inhibits Enzyme McAwesome, Red Molecule and Blue Molecule don’t get together quite as fast as they would with the help of Enzyme McAwesome.

Now say that Enzyme McAwesome catalyzes the vital step in a biochemical pathway that creates ATP, the molecule that stores energy for use in molecular actions. If Enzyme McAwesome is inhibited, ATP gets created much, MUCH slower than it would with Enzyme McAwesome’s help. The cell doesn’t make as much ATP as it’s used to making, and so molecular actions are far less likely to be “funded” in an energy-supplying way. If molecular actions don’t get the energy they need to actually action, the cell shuts down. And there’s the end of the cell.

Organs are made up of cells. If enough cells shut down in an organ, the organ will fail. And if enough organs fail in the human body (or the wrong single organ fails), the person will die.

See what poisons are now? Poisons are simply substances that interfere with important biochemical pathways. They basically throw a block in the marble run, causing backups and overflows, and getting in the way of anything getting where it’s supposed to get. Sometimes they will block a branch of a biochemical pathway and direct the substrates down a secondary path where they create toxic molecules which then go on to make trouble of their own.

Poisons can be pretty much anything.

Lead causes problems by binding to enzymatic, receptor, and structural proteins. It is also structurally similar enough to calcium to interfere with metabolic pathways that use calcium. This makes problems in particular in the mitochondria, the “powerhouse” of the cell where most of the ATP is generated.

Carbon Monoxide “poisons” hemoglobin, interfering with the proper binding of oxygen to heme.

Cyanide “poisons” the electron transport chain, which is a vital component of the biochemical process that makes ATP using glycolysis and the Kreb Cycle. It basically passes off the extra electrons from the process to an oxygen molecule, which then combines with hydrogen to make water. If the electron transport chain is inhibited, the electrons don’t get passed along, and the marble run starts to back up. And then ATP just doesn’t get made aerobically (that is, with the help of oxygen) (that is, the most efficient way to make ATP); the substrates get shunted to the anaerobic pathway (the one that doesn’t require oxygen). That pathway makes less ATP, and also generates lactic acid, which is what you can feel burning in your muscles when you’re exercising beyond your oxygen supply.

This picture is a graphic representation of the Electron Transport Chain, an important series of membrane proteins in mitochondria that help facilitate ATP production. See the blue words with the 'T' shapes pointing out from them? Those are poisons, and the crossbar of the 'T' points to where they interfere with the Electron Transport Chain. Cyanide is the one labeled 'KCN', which is 'potassium cyanide'.

Warfarin is a fun example because it’s a poison…that’s used as a medicine! It was historically used as rat poison. Now it’s used as a blood thinner. Basically, warfarin interferes with the Vitamin-K-dependent formation of gamma-carboxyglutamate, which is essential for the proper function of a number of clotting factors. The upshot is, warfarin “poisons” the pathway that makes clotting factors, which basically “poisons” the clotting cascade. This can be helpful for people who are at risk for conditions relating to over-clot-ification, such as pulmonary embolism and stroke. This can also be very harmful if it’s not carefully monitored.

There's that 'T' shape again, telling you where warfarin interferes with the process. The negative signs also indicate interference or antagonism, and the positive sign indicates facilitation or agonism.

Water can even act as a poison, if there’s too much of it in your system!

So I’m a little unsure about how to advise you to approach poisons in your fiction. I’m sure you can see that poisons are very, very biochemistry-oriented, so it may be difficult as a layperson to navigate the whole poisoning thing in a completely medically accurate way. So you might want to go the way of the not-precisely-medically-accurate-but-at-least-medically-plausible.

Here are a couple of tips to help you out:

-Pick an organ system (like the gastrointestinal system or the neuromuscular system), and keep the symptoms of the poisoning to that organ system. It helps you organize the symptoms instead of flying all over the map in a medically-implausible way.

-Poisons can hit many organ systems at once, but try to keep symptoms to a minimum; if your character turns blue, their hair falls out, their tongue cramps into a ball, their eyeballs pop out, their heart skips every third beat, and they start pooping blood….well, people are going to start rolling their eyes. But if your character gets poisoned and slowly develops vague stomach problems that get worse and worse and worse until she dies in writhing agony…..that’s a little more plausible.

-This is another situation in which lack-of-specificity is your friend. Non-specific symptoms such as gastrointestinal distress (nausea, vomiting, diarrhea), headache, and/or muscle weakness are good ways of avoiding pitfalls of non-believability. You can add them to specific symptoms, but again, think about keeping your specific symptoms to maybe one or two, and fill any “this-doesn’t-look-serious-enough” gaps with non-specific symptoms.

-If you find yourself at a loss, try modeling the symptoms for your made-up poison after a real-life poison. (You don’t have to name the real-life poison in your work; just steal the symptoms. Although, many medical people will be able to recognize which poison you’re borrowing from. Just keep that in mind.) This will help you organize the symptoms to a biochemical distribution without actually having to understand the biochemistry.

For the more biochemically adventurous:

-Try and figure out which cellular process it’s going to interfere with. Remember that cells need food (glucose), oxygen, and water and electrolytes in physiological balance. Some types of cells need to replicate in order to perform their function; all cells need their replication controlled by regulator proteins or else they become cancerous. Many cells are triggered to certain actions by chemical signaling in the body, and many cells are inhibited from performing certain actions by chemical signals. And on and on and on. You can pick any one of these functions to “poison”.

-Try to decide which organs might be most affected by the process you’ve chosen. If you’re interfering with glucose uptake, the brain will be very strongly affected since it’s dependent on glucose and can’t survive on nutritional substitutes (such as ketone bodies) like most other cells can.

-The liver and the kidneys are usually responsible for cleaning poisons out of the blood, so many poisons will hit the liver and/or kidneys hard.

-Try to match the symptoms of the poisoning to the organ system involved. A person with carbon monoxide poisoning won’t necessarily gasp for air, but they’ll be suffocating on a cellular level. A person with an overdose of warfarin will have trouble with bleeding issues; they’ll bruise easily and get nosebleeds and hemorrhagic strokes and all those other things that go along with not being able to clot your blood.

Okay, I think that’s enough from me for now. Where have you seen fictional poisonings? What makes them seem more or less plausible to you?

References:

StatRef! http://online.statref.com

Pictures:

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If you use this as if it were real medical information, I’ll make YOU fight Sir Griswold. (Good stock!)

Don’t Run Away.

Promise?

Okay…

Steel yourself and look at

THIS.

NOOOOOOOOOOOOOOOO!!!

You promised!

This better be worth it.

Oh, it totally is. Today, we’re going to talk about biochemical pathways!

Why?

Um, because they’re awesome.

We are clearly operating on different definitions of the word ‘awesome’.

Okay, how about because they’re important to understanding medicine?

I’m a writer for a reason. It’s your job to understand medicine.

Point taken. Well, how ’bout this then: How often does someone get poisoned in a fictional story?

I’d say in a good story, every character gets poisoned at least once.

Okay, maybe that’s going overboard a little. But poisons are definitely a useful fictional tool; you see them everywhere from Shakespeare to James Bond.

So poisons are all about biochemistry.

That means I have to give you a framework for thinking about biochemistry before I can even think about talking through one of the most widely-used-for-plot-points categories of illness.

Okay. I’ll try to stay awake.

How magnanimous.

I’m the magnanimous type.

So I see.

Okay, Captain Magnanimous, I want you to picture a marble run.

Dude! You are OBSESSED with marbles!

You said you’d bear with me.

Get to the point, Hoppy.

Well, biochemistry is a lot like a marble run.

Uh…………..

Pretend this marble is a molecule of some kind.

We’ll start it out at the top of the marble run. It rolls through a series of maze pieces, like a funnel, or a straight run, or a peg maze. Similarly, the molecule rolls through a series of steps in a biochemical pathway. (The difference between the molecule and the marble is that the molecule gets a structural change with each step.)

By the end of the marble run/biochemical pathway, our marble-molecule might look like this

Or this

Or this.

But regardless, it started out at the top of the marble run, and rolled its way through to the bottom.

So if you put a bunch of marbles through the marble run, you end up with a bunch of marbles at the end. And if you put a bunch of molecules through a biochemical pathway, you end up with a bunch of (altered) molecules at the end.

Biochemistry is totally more complicated than that.

Yeah, it is…but only when you start getting into specifics. I actually just wrote out an explanation of glycolysis and the TCA cycle and the electron transport chain, but it got way too long so I deleted it. Even though it was very marble-y and fun to write.

Geek.

Indeed.

So here’s the main point. All I wanted to tell you is that even though biochemical pathways look scary and complicated, there are only a few things you really need to know.

1) You start with a molecule.

2) The molecule is transformed in a series of steps, usually designated by an arrangement of arrows, like so:

This says: You start out with a molecule called pyruvate. Pyruvate is converted to a molecule called acetyl CoA. The conversion process also releases a molecule of carbon dioxide, converts a molecule of NAD+ to NADH, and uses a molecule of Coenzyme A.

3) If your eyes are glazing over, this is what you can think about instead:

Here’s a longer pathway:

This says: Pyruvate is converted into acetyl CoA. Acetyl CoA is used to convert oxaloacetate into citrate. Citrate is converted into isocitrate. Isocitrate to alpha-ketogluterate. Et cetera. And around and around. This is called the TCA cycle.

If your brain is trying to implode and suck your eyes into a whirling vortex of madness, here’s what you can think about instead:

Random aside: Here’s a mnemonic to help remember the compounds of the TCA cycle in order: “Our City Is Kept Safe And Sound From Malice.” Isn’t med school fun? For more biochemical mnemonics, you can go here.

4) The transformations designated by the arrows are either spontaneous rearrangements into more thermodynamically happy positions, or are facilitated by helper molecules called “enzymes”.

5) If anything goes wrong in the pathway (ie: if one of the arrows/enzymes doesn’t do its job), the molecules going through the pathway will “back up” behind the problem. It’s like marbles backing up behind a block in the marble run.

6) Some biochemical pathways have split points, like forks in the road. Usually molecules like one path more than the other, and will take that path preferentially. Like if a marble has the choice of shooting down a straight run or taking a turn, it’ll usually shoot down the straight run.

7) If there’s a “backup” in the preferred path, molecules have no problem going down the alternate path. Like if the straight run is blocked by a marble backup, the marbles will instead make the turn and go down the previously less favorable path.

——————————————————————————————————-

That might be enough for now. Any questions?

Yeah. All those scary complicated biochemistry pathways up there. . . do you know them by heart?

Nope. Not anymore. But I used to, three years ago. First-year Biochemistry class, baby!

Crazy.

I’m actually happy that I did memorize them at one time, to be honest. It was hard to learn the individual pathways, sure. But when you start seeing how everything fits together, you get this overwhelmingly satisfying mental CLICK, and suddenly you’re just blown away by the beauty of the whole thing.

We are clearly operating on different definitions of the word ‘beauty’.

That may be. But just trust me when I say that life is a beautiful, graceful thing. . . right down to the dance of the individual molecules.

Next time, we’ll throw a wrench in the works.

Stay tuned.

#

References:

Nelson, David L., Cox, Michael M. Lehninger Principles of Biochemistry. 3rd Ed. Worth Publishers, 2000.

Pictures: