The use of poisons in war, specifically poison gas, started in the First World War. But one of the most potent poison gases, nerve gases ever discovered is the compound called sarin. This was developed by the Germans in the 1930s, and taken over by the German military. In the World War II, the Germans stockpiled a lot of sarin, but it was never used. And most of it was discovered by the Russians, as they push through into Germany. All sorts of countries have made and have stockpiled sarin. And most, quite recently, we've seen that the United States going to the verge of military action against Syria, because of the use of sarin in the Syrian Civil War. One terrible use of sarin was back in 1988, when the Saddam Hussein's military in Iraq used it against villages up in the Kurdistan, in the north of the country. Sarin is a very, very powerful nerve agent. It gets into the body, it stops the nervous system working, and even with very low doses causes death. It's not just governments that have made sarin. This Japanese cult called Aum Shinrikyo also had a go at making sarin. And they released some in a town called Matsumoto, in June of 1994, killing seven people. The following year, they carried out the well-known Tokyo subway attack, where they released their homemade sarin in the Tokyo subway. They killed 12 people. A 1000 people at least went to hospital, and even today there are still people suffering the ill effects of that attack. Fortunately, the Aum Shinrikyo chemists weren't very good at their job. The sarin they produced wasn't very pure, and it smelled very badly. If they'd made pure sarin then the death toll would have been much, much higher. Well, how do these nerve agents work? They work by interfering with the biochemical mechanism in which nerve impulses travel from the brain to the muscles. So, this is a nerve cell, and it does look like a piece of wire and in some ways it acts like a piece of wire in transmitting the message. So, how does a nerve cell actually work in chemical terms? Well, let's consider a nerve cell in its resting state, where nothing is going on. Here's the nerve cell. Before it is the previous nerve cell, in front of it is another nerve cell. And it's this line of nerve cells which will ultimately carry the impulse from the brain to the muscle. Well, the resting state those potassium ions inside the cell, there's sodium ions outside the cell, and the cell has a slight negative voltage. At the business end of the cell there's a little molecule sitting there. This is called the neurotransmitter, and the job of the neurotransmitter is to jump across the synapse, to trigger the next nerve cell in the line. The signal comes down the line, the neuron becomes excited and passageways in the cell wall open up, and these passageways are sodium channels. They will allow sodium to flow into the cell. So, sodium flows from outside the cell into the cell, which means that the voltage becomes positive. So the neuron is excited. It's now a plus 30 mV, and the neurotransmitter is released. Now, this neurotransmitter is a little molecule called acetylcholine. It's released, it crosses the synapse and when it gets to the nerve cell on the other side, it then excites that one, and the message continues down the line. So, the nerve cell that we're looking at now has to get back to its original state. Passageways in the cell wall open, these are potassium channels and potassium is released. The final thing is that ion pumps redistribute the sodium and potassium, so the potassium goes back in the cell, the sodium comes out, and we're back where we started, we're back at the original state. Now, the neurotransmitter has done its job, so at some point it either has to go back to where it started or it has to be removed. And it's removed by being destroyed by a particular enzyme called acetylcholinsterase. And this whole process takes two milliseconds. Very remarkable piece of chemistry. But remarkable piece of chemistry, what happens when we interfere with it? Sarin interferes at the neurotransmitter stage. Suppose, we have excess of the neurotransmitter present. What will happen? Well, it mean we get continued nerve stimulation. Even though there is no signal coming down from the line, from the brain, the nerve is still stimulated, and that means that the muscles at the end of the nerve are still activating. This leads to twitching. It leads to convulsions. It leads to paralysis and death. It often starts with blindness, due to the effect on the eye muscles and the eye nerves. Now, under what circumstances would we have excess of the neurotransmitter present? Well, the concentration of the neurotransmitter is regulated by this enzyme called acetylcholinsterase, which converts the acetylcholine into inactive choline. What sarin does is block the action of that enzyme, so that the excess acetylcholine cannot be destroyed, and therefore will be present in excess. Well, I don't know if you've seen this movie, it's called ''The Rock''. It was made a few years ago, and it stars as the heroes, Sean Connery and Nicolas Cage, with Ed Harris as the villain. Well, in this movie, some renegade U.S. soldiers steal some sarin containing chemical weapons, and take over the island of Alcatraz in San Francisco Bay, and threatened to fire these weapons at San Francisco. So, Nicolas Cage and Sean Connery are sent into Alcatraz to defeat this dastardly scheme. In a scene towards the end of the movie, Nicolas Cage is exposed to sarin when one of these things go off, and very dramatically he pulls out this syringe he's been given earlier on, and he's stamps himself in the chest with a syringe. And then everything's fine, and the bad guys are dealt with. And Nicolas Cage gets the girl. And there's a happy ending. Now, what was in the syringe? The answer is, a naturally occurring chemical called atropine. And atropine is the antidote to sarin. The reason it's the antidote to sarin is because it has the opposite effect. Whereas sarin inhibits the action of acetylcholinsterase, the enzyme atropine inhibits the action of acetylcholine. So if you have excess acetylcholine present, atropine will prevent it from acting. So, the atropine does the opposite to the sarin. So provided the doses are about balanced, then it's going to work as an antidote. On the other hand, if you take atropine just as atropine, not as an antidote, then it will be toxic, because it's going to inhibit this action of your neurotransmitter. And as you can see there, there is an LD_50 for atropine in rats by all administration. Now, atropine, as I said, is a naturally occurring compound and it comes from the plant Atropa belladonna. So, it gets its name from the atropa part. But what about the belladonna? Well, belladonna is Italian for beautiful lady. And one of the effects of atropine is that if atropine is placed in the eye then the pupil dilates, so the pupil becomes bigger, and many people consider this to be beautiful, hence belladonna, beautiful lady. And in fact, one of the uses of atropine is in optometry, because if you put it in someone's eye, and you dilate the pupil to make it bigger then it's easier for the ophthalmologist to see inside. Provided it's only on the surface of your eye it's not going to do you any harm at all. But of course, if it's ingested then, as we know, it's toxic. I mentioned at the beginning of this lecture that one of the reasons that poisoning is less common nowadays than in the old days is because it's much more difficult to get hold of these very, very poisonous substances. However, one group of people who can get hold of these substances relatively easily, are chemistry professors. And this case here involves a professor of biochemistry, Paul Agutter, who used to be at Napier University in Edinburgh, Scotland. And he was convicted of poisoning his wife with atropine, which he had obtained ostensibly for research purposes. So, how did Agutter do it? Well, he put atropine in his wife's gin and tonic. Now, if a wife is murdered then of course one of the first suspects is going to be the husband. And Agutter knew this, so he laid a false trail to try and mislead any investigators. He went to a local supermarket and took some of the bottles of tonic water, and spiked them with atropine, and then return them to the supermarket. His idea was, by having random people around the town having mild atropine poisoning people would think this is some kind of serial killer, or maybe someone with a grudge against the supermarket, or the drink manufacturer, rather than a husband trying to get rid of his wife. Unfortunately, for him, his scheme unraveled, and that is because the amount of atropine he put in the tonic bottles was less than the amount of atropine that he put in his wife's drink. These things, of course, are very easy to measure using a technique such as HPPLC. So it was very clear to the police that it was actually a husband-wife case, rather than a mass poisoner. Well, fortunately, his wife got medical treatment, she survived. And Agutter was convicted only of attempted murder, and he served seven years in prison. Interestingly, after his release from prison, he started to work for the University of Manchester, and they asked him to teach a course on medical ethics.
