6:14 p.m. September 4, 2013

Sarin: The Ultimate On-Switch

The whole world is talking about Syria. Specifically, the whole world is talking about how the Syrian army is alleged to have used sarin gas against its own people -- including children -- thus apparently obligating America to get itself into another war.

We’ve all seen the horrific effects of sarin, from the YouTube videos coming out of Syria or from footage of the 1995 Tokyo subway attack. But what exactly is sarin, where did it come from and what is it capable of?

Time for another explainer!

Sarin gas has humble roots as an organophosphate pesticide. In 1938, researchers at the German chemical research conglomerate IG Farben discovered the chemical during their search for stronger pesticides. The man who accidentally discovered sarin (and its nerve agent relatives) was Dr. Gerhard Schrader, head of the plant-protection group, a team of researchers tasked with developing new, cheaper synthetic pesticides to reduce Germany’s dependence on imported food. His systematic syntheses of different organic (carbon-containing) compounds led to several dead ends in terms of practical, usable insecticides, but he was undeterred. Soon, he moved into working with phosphorous. (Yes, despite its cultural connotations, an “organic compound” is just something that contains carbon.)

The organophosphates turned out to be very successful at killing insects. Schrader and his team continued their systematic work, trying out different combinations of molecules stuck to a central phosphorus atom. Then he threw a cyanide in the mix. Cyanide is a stupidly simple molecule; it’s just one carbon atom triple-bonded to a nitrogen atom, but it is nevertheless quite toxic. And although the compounds were synthesized in a fume hood to remove potentially harmful gases, Schrader found himself affected by his new chemical. Pin-point pupils and visual impairment became breathing problems and blindness; suffering from the effects of a yet unnamed chemical, Schrader spent two weeks in the hospital before he could see again.

Ever the scientist, upon his release Schrader went right back to work with this cyanide-containing organophosphate. Through careful, deliberate exposure, he and his assistant Karl Küpper probed the strange, powerful physiological effects. Also, the compound smelled faintly of apples. Curious and worried that they were indeed poisoning themselves, their symptoms escalating, they sent the compound for toxicological testing.

The man for the job was a German toxicologist named Dr. Gross.

To Schrader’s dismay, his compound Le-100 turned out to be far too toxic to mammals for use as a pesticide; it killed everything they tested it on. And quickly. Dr. Gross’ experiments on apes found that as little as one tenth of a milligram of the newly named Le-100 (an amount approximately the mass of a third of a grain of salt) per kilogram of body mass resulted in a nasty response: prodigious drooling and sweating, pin-point pupils, constriction of the bronchial tubes in the lungs, vomiting, cramping, convulsions, gasping for breath, the slowing of the heartbeat and respiratory rate, all culminating in death by paralysis of the breathing muscles.

So no, not a great insecticide.

He disclosed his findings to the War Office per the official Reich ordinance that all discoveries of potential military significance be reported and moved on.

That is, until the rather misleadingly named Army Gas Protection Laboratory, a large lab with over 300 scientists working on chemical warfare defense and chemical weapon development, called Schrader in for a live-demo. The potency of Le-100 was so impressive that one Army scientist deemed it tabu (taboo in English), expressing concern that it was too strong. The substance was named Tabun. Appropriate. From there it’s a pharmaceutical, military-industrial love story. IG Farben was still squeamish about getting into bed with chemical warfare due to the potential for negative PR for their commercial products, so they were happy to let the Army take over tabun development and production. They eventually got over their trepidation; in the years that followed, IG Farben became synonymous with chemical death, as they cooperated closely with Nazi leadership, manufacturing the pesticide Zyklon B that was used to gas millions of people to death in extermination camps.

Meanwhile, as the German Army was going to town on tabun development, Schrader was back in his lab, working with his organophosphates, trying to make safe insecticides. Ever the tinkerer, the way most synthetic chemists are tinkerers I suppose, he stuck a fluorine into his organophosphate and holy shit: it appeared that his new compound’s toxicity against insects was really fucking high. Yet again, he sent a sample to his pal Dr. Gross for analysis.

Gross killed a bunch of lab animals, which to be fair, is basically what he was paid to do, and discovered that this new compound was even more toxic than tabun. This is significant because at the time, tabun was far and away the most toxic substance known to man. Another new compound from Schrader, another new compound ruled out for usage as an insecticide. Hard times for a plant-protection chemist.

Naturally, Gross sent the report to the German War Office where further testing showed the newly-dubbed Substance 146 was not only more toxic than tabun, it was also odorless, more stable, and less likely to be destroyed by explosion. It even evaporated more quickly than tabun, which lingered in the environment, making it non-ideal for battle. However, tabum was already in mass production; the 12,000 tons of tabun stock reported at the end of the war was enough to kill 60 billion people. So Substance 146 was given to the basement of the Spandau Citadel, where small amounts were produced for testing. It was also given a name, an acronym memorializing the individuals involved in its development: Gerhard Schrader and IG Farben board member Otto Ambros, and from the Army Ordnance Office Colonel Rüdiger and Hans-Jürgan Van der Linde. Schrader, Ambros, Rudiger, and Van der Linde. SARIN.

But Schrader’s noteworthy position at the start of the acronym is misleading. From Jonathan Tucker’s book “War of Nerves: Chemical Warfare from World War I to Al-Qaeda:”

“Although Schrader worked intermittently on a manufacturing process for Sarin, the Army expanded its technical staff and asserted full control over the development effort, limiting his involvement. Schrader resented being excluded and complained that the engineers at Spandau were mismanaging the process developmental effort and causing lengthy delays. He was also suspicious of the secrecy surrounding the physiological laboratory where Dr. Wirth and his colleagues were conducting experiments with tabun and sarin.

“When Schrader traveled to Spandau periodically to advise on technical issues, he was never allowed near the medical clinic and physiological laboratory in Building 15. Mystified, he suspected that some type of illicit activity was going on there, possibly experimentation on humans.”

And that’s how sarin came to be created by plant-protector Gerhard “father of the nerve agents” Schrader.

About that. As I’m sure you’ve heard bandied about in the news, sarin is a nerve agent. However, not all Sarin explainers are created equal. For example, both ABC News and Business Insider have called it “an ‘off-switch’ for the body,” which is ridiculous and literally the opposite of what sarin does to a body. (RS)-Propan-2-yl methylphosphonofluoridate is a doozy of an acetylcholinesterase inhibitor: sarin is the ultimate on-switch.

Here’s how it works. When a brain decides to do something like move its meat sack through space, it needs an efficient way to communicate with all those relatively far-away muscles. Likewise, the muscles must receive some signal that they need to contract. To this end, the brain relies on a network of motor neurons. These originate, rather redundantly, from the motor cortex of the brain and extend out from the spinal cord and into the muscles. Where the tip of the axon - the long bit that extends from the cell body of the neuron - comes close to whatever it needs to talk to, it forms a synapse. This specific kind of synapse between axon ending and muscle fiber is called a neuromuscular junction. Ta-da!

Say I want to kick somebody in the gonads. My brain, both originator and perpetrator of this idea - fires off a nerve impulse that travels down the axon. (It’s kind of like the game “Telephone”, or um, using a landline telephone.) Once the message (nerve impulse) gets to the neuromuscularjunction, it triggers all these little vesicles - wee membranous pouches - to pop. Sploosh!

The vesicles contain a neurotransmitter. In the case of my kicking a crotch (voluntary skeletal muscle movement), the neurotransmitter is acetylcholine.

It’s kind of like throwing a water balloon. Acetylcholine splurts forth from the axon ending into the synapse, rushing towards the loving metaphorical arms across the void, acetylcholine receptors. That’s when the magic happens. You see, when a neurotransmitter and a receptor love each other very much, sometimes they hold each other in a very tight and special way and make a baby. And by that I mean another nerve impulse. Upon this biochemical embrace, a new nerve impulse is triggered along the muscle fiber membrane, causing the fiber to rapidly contract.

I should note at this point that while acetylcholine is the only neurotransmitter used in the motor division of the somatic (voluntary) nervous system, that’s certainly not the only place acetylcholine is found.

It’s also used in the autonomic nervous system, where all the shit your body does on its own happens. Digestion, pupil dilation, breathing, heart rate, making pee, sexual arousal, blinking, all of that. Oh, and acetylcholine works on the central nervous system as well, the part of you that processes information from the body and coordinates appropriate responses.

With acetylcholine snuggled into its receptor, the on-off switch is firmly in the on position. But this switch cannot stay on, or else bad things happen.

To get things to stop firing ON! ON! ON!, an enzyme called acetylcholinesterase breaks down the acetylcholine into two constituent parts. This break-apart action rapidly clears the neurotransmitter from its receptor, which turns the switch back off. This is absolutely critical. Without it, the lub-dub of a heartbeat would just be lub. Breathing in and out would become just one or the other. Messages all over the body would scramble as nerve impulses were continually transmitted, switches flicking on, on, on with nothing to end the stimulation.

This is where sarin comes in. Sarin keeps your body from turning off its panoply of neural switches. To continue the biochemical love-story metaphor, sarin and acetylcholinesterase are way more sexually attracted to each other than acetylcholinesterase and acetylcholine. Sarin, all bad decisions and irresistible dimensions, binds to the active site of the acetylcholinesterase, the special love nook where acetylcholine usually does the dirty. But not today. Sarin seductively grabs acetylcholinesterase, throwing off its fluoride with reckless abandon, and the two star-crossed molecules become one useless, biologically inactive phosphoester. Scorned and unable to protest, acetylcholine is left alone and balls deep in its receptor, doomed to trigger a continually transmitted nerve impulse.

Much like the symptoms Dr. Schrader experienced after coming into contact with his yet-unnamed nerve gas in his lab, initial symptoms following sarin exposure include runny nose, pupil constriction, and a feeling of tightness in the chest. Greater exposure to sarin results in a massive discharge of the parasympathetic nervous system - lots of switches firing GO! This presents as SLUDGE: salivation, lacrimation, urination, defecation, gastrointestinal distress, and emesis. Victims drool, cry, piss, shit, cramp, spurt, and vomit. All the signals are reading go; everything starts to happen at once.

This phase is followed by more loss of control, with bodies twitching under the unmitigated effects of their own acetylcholine, until, unable to breathe out, they suffocate.

Death by sarin is a gruesome hijacking of the mammalian body’s internal communication system. For treatment to work, it must be administered immediately. That treatment involves paralidoxime, a cholinesterase reactivator, and atropine. A competitive antagonist, atropine can bind a type of acetylcholine receptor (muscarinic) without actually activating the receptor. Thus, it can essentially undo or counteract the ON! ON! ON! messages sent to the parasympathetic nervous system (guts, heartbeat, stuff you don’t have to think about) by getting in the way of acetylcholine. However, atropine doesn’t work on the acetylcholine receptors that control muscles (nicotinic), so those will continue to fire. There’s something darkly poetic about using a naturally occurring toxin, one with which we humans have a long and storied history, to fight the devastating effects of one of our relatively new, man-made horrors. Atropa belladonna, better known as deadly nightshade, versus a vicious lab-born killer. Not many plants stand up to man’s war toys.

After WWII, British spies tried to recruit the father of nerve agents to develop chemical weapons for Britain. However, their interest quickly evaporated after Schrader said he would like to work for them, but only for “peaceful ends”.

"I should like to assist in improving nutrition, but not in inflicting new wounds."

By the time they contacted him in 1947, he was back in his lab, and had already developed a new insecticide against the Colorado potato beetle.

A scientist devoted to the protection of plants, in his attempts to develop new pesticides, gave the world toxins of unbelievable magnitude. And wouldn’t you know it, our best line of defense against sarin comes from a plant.