Poison Pain, Pus and Poison: The Search for Modern Medicines


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This is Walton Hall in Yorkshire.

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In 1835, it was home to a wealthy and somewhat eccentric gentleman.

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They said he could be seen regularly walking the grounds bare-footed,

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and in the company of an ageing donkey.

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Now they must have been a pretty shabby pair

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but, between them, they took part in one of the more extraordinary

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experiments of the 19th century.

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An experiment that would lead to significant breakthroughs

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in medicine and in surgery,

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and would transform our understanding of poisons.

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Come on then.

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Pain, Pus And Poison has charted the many colourful characters

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who, over the past 200 years, created the medicines

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which protect us from pain, infectious disease and even death.

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Through their heroic efforts,

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chemicals almost magical in their effects were discovered,

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scrutinised, and finally exploited.

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In this programme, I'll reveal the remarkable science behind perhaps

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the most unexpected source of many modern medicines.

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Poisons.

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Poisons that include the planet's most deadly substances.

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A couple of kilos would kill every human on the planet.

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From the natural world to the man-made,

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it's a tale of greed, tragedy, hope and chance.

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What started out as a science expedition looking at bugs

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turns into a cancer therapy.

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To me, I think that's one of the wonders of science.

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So just how far can we go into unlocking the benefits of poisons?

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All medicines are poisons and all poisons should be considered

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as potential medicines.

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This is the story of how we have turned killers

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into cures.

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Poisons have, throughout history, been used to take life,

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whether by suicide, assassination or murder.

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And yet, until the 19th century,

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surprisingly little was known about how they actually work.

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Someone who helped change that was Charles Waterton,

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the colourful squire of Walton Hall.

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He was considered very eccentric.

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He used to sometimes hide under tables

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and bite people's legs at the dinner table.

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He was double-jointed.

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He could scratch behind his ear with his big toe.

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He was an avid tree-climber.

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He climbed trees into his 80s. That's quite strange.

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As well as being an eccentric,

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Waterton was also a man with a passion for knowledge.

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He travelled the globe, collecting the exotic and

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the unusual, not always simply for scientific study.

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He created a taxidermy piece after a customs officer had upset him by

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charging extra duty on the specimens he'd brought back from Guyana.

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He changed the rear end, the arse of a Howler Monkey,

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to look like this customs officer's face,

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which is possibly the perfect insult.

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Waterton spent nearly 20 years living in the Amazonian rainforest,

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where he befriended one of the Amerindian tribes,

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called the Macushi.

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Now what Waterton was really interested in

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was a closely guarded secret -

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a poison that could kill almost any animal,

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and which occasionally they used to kill each other.

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He managed to get the recipe from the Indians.

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It's got some really interesting ingredients.

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We've got the fangs of the Labari Snake,

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and there's also apparently some Black Ants you pound in,

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which are so venomous their sting alone produces a fever.

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But it's actually not those things.

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The key ingredient is a vine which grows in these wilds,

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which is called Wourali.

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It is from this that the poison takes its name,

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and this is the principal ingredient.

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This vine was later identified as strychnos toxifera.

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And the poison from it is known today as Curare.

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Now, these are real samples that Waterton brought back

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200 years ago -

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a bowl in which you'd sort of mix up the ingredients,

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and these are the poison darts.

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In fact, the poison is the black stuff on the end.

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That is Curare. And although it is 200 years old,

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it's still active so I'm not going to touch it.

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Now, Waterton himself brought it back because Europeans

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were absolutely fascinated by Curare and no-one else had

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succeeded in getting the really good stuff in quantities.

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Certainly not enough to do proper experiments with.

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Back home, Waterton was approached by leading vet

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Professor William Sewell,

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and eminent surgeon Sir Benjamin Brodie,

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who wanted to find out exactly how Curare killed its victims.

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Brodie had already tested the poison on small animals,

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but now wanted to experiment on something larger.

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So they used a donkey.

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They injected the unfortunate donkey with enough Curare to kill it.

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Then when it collapsed and stopped breathing,

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they quickly performed an emergency tracheotomy.

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What you do is you get a knife

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and you slit your way into the windpipe here,

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and then what they did is they inserted a pair of bellows into

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the windpipe and pumped away.

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And they really had very little idea of what they were doing.

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They didn't know how long they would have to do it for.

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After about two hours,

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the donkey sort of recovered enough

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to look up and sort of stare at them.

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So they stopped, and the donkey then collapsed.

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So back to the bellows again.

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They kept this up in total for about four hours.

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Until finally, as Waterton wrote in his journal,

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the pumping had saved her from her final disillusion.

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She rose, she walked about without obvious agitation or pain.

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Yes.

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Waterton, Sewell, Brodie and, of course, the donkey,

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had demonstrated something remarkable.

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A discovery that would have an unexpected

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and far-reaching impact.

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They had shown that curare acts on specific muscles,

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including those that enable you to move and breathe.

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Whereas other muscles, including, crucially, the heart,

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were completely unaffected.

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As long as you can keep the patient breathing,

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he, she or it, should survive.

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The key aspects of curare is that it's a muscle relaxant.

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All your voluntary muscles will stop working,

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including the respiratory muscles.

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The three scientists had shown it's possible to keep a patient alive

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while their body is rendered immobile, relaxed by curare.

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Now, in the early 1800s,

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this discovery had no obvious application.

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But 100 years later, it would transform surgery.

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In the mid 20th century, one of my favourite self-experimenters,

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Dr Fred Prescott,

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deliberately injected himself with a pure form of curare

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to demonstrate that it is safe to use

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as a form of muscle relaxant in surgery.

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In fact, since the 1950s, most people who've had major surgery

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will have benefited from curare or one of its modern equivalents.

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And the donkey, she was retired to Walton Hall.

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Charles Waterton wrote in his diaries,

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"She shall be sheltered from the wintry storm.

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"And in summer, she shall have the finest pasture.

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"She will end her days in peace."

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In fact, she did live another 25 years.

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And when she finally died in 1839,

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she got her own obituary in the local paper,

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detailing her contribution to medical science.

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In Victorian Britain, life was harsh and often cut short.

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Life insurance suddenly became a boom industry.

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This led to a surge in financially-motivated murders.

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Many by poison.

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These poisonings would, in turn, have unexpected consequences

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for pharmacy and forensic science.

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One of the most high-profile Victorian cases

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was a woman called Mary Ann Cotton.

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She was married four times.

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Three of her husbands, heavily insured, all died.

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The one who survived seems to have done so

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because he refused to take out insurance, so she left him.

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In all, 10 of her children died

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of what appeared to be gastric-related illnesses.

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Tragic and terribly sad,

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but fortunately, most of them were insured.

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Her mother, her sister-in-law and her lover

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also died and in each case, she benefited.

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By 1872, the unfortunate Mary Ann

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had lost an astonishing 16 close friends

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or family members.

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But there was one left.

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Her seven-year-old stepson, Charles Cotton.

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Now, she tried to give him away to the local workhouse,

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but they wouldn't have him without her.

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Young Charles soon died.

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The manager of the workhouse, however, got suspicious

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when he heard about the death of the child and he contacted the police.

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They investigated and exhumed the body of young Charles.

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They suspected foul play.

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And, not surprisingly, wondered if Mary Ann had poisoned him.

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BELLS PEAL

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They thought they knew how she'd done it.

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With arsenic.

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Arsenic was an excellent way to kill somebody.

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It's known as a cumulative poison,

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which means that you don't excrete the dose.

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So in other words, the more you take,

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it builds up more and more in the body.

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And it was very easy to administer in food.

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So it just looked like somebody was dying of natural causes.

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The trial of Mary Ann Cotton would hinge on whether

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they could find traces of arsenic in the body of Charles Cotton.

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Now, forensic science was still in its infancy,

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but they did have a good test for arsenic.

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The reason for that is,

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there was an awful lot of arsenic-poisoning around.

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This test is called the Reinsch test.

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And it was the one used to discover

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whether Mary Ann had poisoned little Charles.

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A sample from the boy's stomach and intestines

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was heated with acid and copper.

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If arsenic was present, the copper would turn dark grey.

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And when placed on paper soaked in mercury bromide,

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produce a tell-tale yellowy-brown stain.

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And when they did this test on the body of poor little Charles,

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they discovered that he had indeed died of a lethal dose of arsenic.

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His stepmother Mary Ann

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was convicted of his murder on the basis of this

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and she was hanged in Durham jail in March, 1873.

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She was never taken to trial for the mysterious deaths

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of her mother, three husbands, two friends

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and 10 other children.

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Throughout the 19th century, tales of sinister poisoners

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and unfortunate accidents filled the newspapers.

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And it was because arsenic was such a silent and prolific killer

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that some of the earliest techniques in forensic science were developed.

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But arsenic was about to do more than that.

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It was about to shape the development

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of the modern drug industry.

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Now, I'm feeling quite nervous

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because this stuff is really, really nasty.

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It actually is a mineral,

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and even a tiny, tiny amount,

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less than a hundredth of an ounce, would kill you.

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As a poison, it is almost unrivalled

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because it's completely tasteless, dissolves in hot water

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and it takes so little to kill.

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I'm going to put that back in there and then...

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Ooo! Go and wash my hands.

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Arsenic trioxide was marketed as a rat poison.

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It was cheap and easily available.

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Children would blithely collect it from the shops,

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along with tea, sugar and dried fruits.

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A fact satirised in this Punch cartoon from 1849.

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And yet there was clear evidence of it being used to murder people.

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So pressure was growing to bring this deadly poison

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under some sort of control.

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The Pharmaceutical Society,

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along with what became the British Medical Association,

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got together in 1849, went to Parliament

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and lobbied for a new law to actually stop these poisonings.

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As consequence, a new act was passed which was the 1851 Arsenic Act,

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which greatly restricted the sales of arsenic.

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The new act said that if you were selling arsenic over the counter,

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then you had to keep a record.

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You also had to know the person you were selling it to.

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And finally, in future, all arsenic

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would have to be coloured with soot or indigo.

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So presumably, if your husband or wife was trying to poison you,

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then you had a better chance of detecting it.

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It had even been proposed

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that women should be banned from buying arsenic.

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But that measure didn't make it onto the statute book.

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Although the act restricted who could buy arsenic,

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it made no mention of who could sell it.

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So inevitably, the deaths continued.

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A few years, and many murders later,

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Parliament finally introduced further laws

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to restrict the sale of the more obvious poisons.

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More importantly, they also created the trade of chemists and druggists.

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The Arsenic Act and other acts that followed

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finally brought arsenic and a whole range of other dangerous chemicals

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under some sort of control.

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Now, I do think it is gloriously ironic

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that it was from all these poisonings, accidents and murders

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that the modern, legitimate business of pharmacy emerged.

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At the start of the 19th century,

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poisons had been mysterious and deadly compounds.

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Convenient for killing yourself or others.

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By the middle of the century, a more rational understanding

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of how they worked was emerging.

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And along with a legal and professional framework

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designed to control their use,

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it would lead to a new era of scientific discovery.

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This is belladonna, deadly nightshade.

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And there is certainly enough there to kill me.

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Now, belladonna in Italian means beautiful lady.

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And that's because in the past, elegant ladies

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would get the juice from this plant

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and they would use it to dilate their pupils

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in the hope that it would make them look more attractive.

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In the 19th century, they managed to isolate the active ingredient

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from the belladonna plant.

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It's a substance called atropine.

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And ophthalmologists started to use this to help them examine the eye.

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Now, I have the modern equivalent here.

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And I'm going to put some in my eye to see what happens.

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Ooo! That does sting.

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Over the last few minutes,

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the focus in this eye has gradually gone.

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And I think you can tell that my pupil

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is a great deal bigger in this eye than that eye.

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But am I more attractive?

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One of the reasons why having a big pupil

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is supposed to make you look more attractive

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is because when you look at somebody

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and you find them sexually attractive, then your pupils expand.

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So it's really just me saying to you,

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at this moment, I find you very, very attractive.

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And that's why you find me very, very attractive.

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Atropine is extremely toxic

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and ladies dying to look more beautiful

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were at risk of doing just that.

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And yet, oddly enough, the best treatment for atropine overdose

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turned out to be another poison.

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In 1864 in Prague,

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a doctor was summoned to treat four prisoners

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who had broken into a local dispensary,

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and, thinking they were drinking alcohol,

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had drunk a large quantity of liquid containing atropine.

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When the doctor got there, they had clear signs of atropine poisoning.

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The men were seriously ill, lying prostate on the ground,

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vomiting profusely, with these huge dilated eyes.

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The doctor had no idea how to treat them.

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Then an ophthalmologist friend of his suggested something radical.

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Poison the men even further.

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But this time, with a different poison.

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Extract of Calabar bean.

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Calabar beans contain a number of pharmacologically-active alkaloids,

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one of which is physostigmine,

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which constricts the pupils.

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Unlike atropine, which dilates them.

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The hope was it could also reverse

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the other more serious effects of atropine.

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The doctor felt he had nothing to lose,

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so he took the man who was sickest,

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whose temperature had gone up

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and who really looked as though he was on the brink of death.

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And he got him, not without difficulty,

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to consume some of this second poison.

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Within a few hours, his temperature had come down.

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Within a day, he was completely cured.

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Calabar beans and atropine have opposing actions.

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They can be used to cancel each other out.

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So effectively, one can be used

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as the antidote to the other, either way around.

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And it wasn't long before poisons began to be commonplace

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in a physician's drug cabinet.

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In fact these, days, atropine is often used

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to reverse the effects of insecticide poisoning

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and it's also used to treat some forms of heart disease.

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During the 19th century, researchers looking into poisons

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were, on the whole, trying to find ways to make them more productive,

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more beneficial.

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At the start of the 20th century,

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things took an altogether bleaker, darker turn.

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World War I.

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It would leave 17 million people dead or missing in action.

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It was a living hell.

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And it was made even more hellish by the work of industrial chemists.

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And during 1917, troops based in Ypres, Belgium,

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reported a strange peppery smell in the air

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and a golden, shimmering cloud that surrounded their feet.

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Within 24 hours, they had started to itch uncontrollably.

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And they came up in horrible, painful blisters

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and vile, incurable sores.

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Those who had inhaled too deeply started to cough up blood.

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The troops had been poisoned by mustard gas.

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Gas masks like this one were state of the art at the time,

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but they were pretty useless against mustard gas.

0:22:560:22:59

The problem is, mustard gas can be absorbed through the skin.

0:22:590:23:03

Even if you were fully clothed, you were not fully protected.

0:23:030:23:07

Gasping, spluttering, drowning,

0:23:090:23:11

it could take up to six weeks to die,

0:23:110:23:14

and it was a terrible death.

0:23:140:23:16

Now, mustard gas was not the first of the poison gasses,

0:23:160:23:20

it was actually one of a number that had been weaponised

0:23:200:23:23

by the Kaiser Wilhelm Institute

0:23:230:23:25

under the directorship of a man called Fritz Haber.

0:23:250:23:29

Fritz Haber was a professor at the prestigious University of Karlsruhe.

0:23:300:23:34

And was married to fellow chemist Clara Immerwahr.

0:23:340:23:37

Haber would go on to win a Nobel Prize in chemistry,

0:23:400:23:44

but he also played a major role in the manufacture of chemical weapons.

0:23:440:23:48

He really pressed the Germans, who...

0:23:490:23:52

The German military didn't have much regard for science.

0:23:520:23:55

..pressed the Germans to see what science could do

0:23:550:23:57

in providing them with explosives and chemical weapons,

0:23:570:24:00

and he oversaw the first use

0:24:000:24:01

of chemical warfare on the Western Front.

0:24:010:24:04

He saw it as an efficient way to fight a war.

0:24:070:24:11

And he didn't think it was especially inhumane.

0:24:110:24:14

After all, he said, death is death, however it is inflicted.

0:24:140:24:18

His wife, Clara, pleaded with him to stop working on gas warfare.

0:24:220:24:27

He angrily and publicly denounced her as a traitor.

0:24:280:24:32

Gas warfare was an horrific, but extremely effective new weapon.

0:24:390:24:43

It not only crippled and killed,

0:24:430:24:46

but also instilled terror right across the battlefield.

0:24:460:24:49

Casualties from the first use were estimated at 5,000 to 10,000 dead,

0:24:520:24:55

with many, many more injured.

0:24:550:24:58

And Haber was delighted, as were the German military.

0:24:580:25:01

Haber was promoted to captain and he returned to Berlin in triumph,

0:25:020:25:07

but the couple continued to argue

0:25:070:25:10

because Clara was deeply unhappy with what he was doing.

0:25:100:25:14

Haber, however, felt that he had an absolute scientific

0:25:140:25:19

and patriotic duty to continue working in chemical warfare.

0:25:190:25:22

Finally, and tragically, Clara took matters into her own hands.

0:25:240:25:28

In the middle of the night,

0:25:370:25:39

Clara silently removed her husband's pistol from its holster.

0:25:390:25:43

She stepped outside.

0:25:530:25:55

And then she shot herself through the heart.

0:25:550:25:59

Later that day, Fritz Haber left for the Eastern Front

0:26:040:26:07

to oversee the next gas release against the Russians.

0:26:070:26:11

He left behind his grieving 13-year-old son,

0:26:130:26:17

who had been the one to discover his mother's dead body.

0:26:170:26:20

Haber continued to enthusiastically promote the use of poisoned gas.

0:26:240:26:29

And his colleagues would go on to develop even more deadly nerve gasses.

0:26:290:26:33

One reason why World War I became known as the chemist's war.

0:26:340:26:38

But the story of mustard gas does not end here.

0:26:420:26:45

20 years later, with World War II looming,

0:26:500:26:53

researchers at Yale University's School of Medicine

0:26:530:26:56

retreated to their labs to try and create antidotes to mustard gas.

0:26:560:27:00

They feared a repeat of World War I.

0:27:050:27:07

But what they discovered would lead them

0:27:090:27:11

into a very different kind of battle.

0:27:110:27:13

Two of the doctors involved were Louis Goodman and Alfred Gilman.

0:27:140:27:18

Working these libraries, they delved into the medical records

0:27:230:27:27

of soldiers who had been exposed to mustard gas in the First World War.

0:27:270:27:31

And what they found, amongst other things, was that these soldiers

0:27:310:27:35

had surprisingly low white blood cell count.

0:27:350:27:39

This chance discovery would lead to a radically new treatment

0:27:400:27:44

for one of our greatest killers. Cancer.

0:27:440:27:47

Cancer occurs as a result of mutations in the cells of DNA.

0:27:510:27:55

These genetic mutations either promote excess cell growth

0:27:550:28:00

or remove the normal safeguards that limit cell division.

0:28:000:28:04

Either way, the cell begins to divide uncontrollably.

0:28:040:28:07

One type of cell that is particularly prone to mutation

0:28:090:28:12

is the leucocyte, or white blood cell.

0:28:120:28:15

Goodman and Gilman thought to themselves,

0:28:170:28:19

if mustard gas can destroy normal white cells,

0:28:190:28:23

perhaps it can also destroy malignant ones.

0:28:230:28:26

It was certainly worth a go.

0:28:260:28:28

After successful animal trials,

0:28:310:28:32

they looked for a human volunteer

0:28:320:28:35

with white blood cell cancer to test their theories on.

0:28:350:28:38

They found a patient with advanced lymphoma,

0:28:390:28:42

known to us only by his initials, JD.

0:28:420:28:45

These are JD's original medical notes,

0:28:480:28:50

which were lost for nearly 70 years.

0:28:500:28:53

And I'm the first person outside the Yale medical community

0:28:530:28:56

to lay my hands on them.

0:28:560:28:58

They tell a fascinating and poignant story.

0:28:580:29:02

JD was a Polish immigrant in his 40s. A metal worker.

0:29:040:29:08

He was riddled with cancer and had a massive tumour on his jaw.

0:29:090:29:13

When he first came in, the tumour had progressed

0:29:150:29:18

to the point where he could not swallow,

0:29:180:29:20

he could not sleep at night,

0:29:200:29:22

he could not fold his arms across his chest

0:29:220:29:25

because the lymph nodes in cancer under his arms were so massive.

0:29:250:29:29

And he was really encased front and back by tumour, and up to his face.

0:29:290:29:34

And he was just absolutely miserable.

0:29:340:29:37

His doctors tried everything they could.

0:29:400:29:42

But the prognosis was not good.

0:29:430:29:45

They had a case conference and concluded it with this line,

0:29:480:29:52

"the patient's outlook is utterly hopeless on the present regiment."

0:29:520:29:56

With nowhere else to turn, JD agreed to try the experimental drug,

0:29:580:30:02

based on deadly mustard gas.

0:30:020:30:04

The notes say that at 10:00am on 27th August, 1942,

0:30:080:30:13

they gave him the first injection

0:30:130:30:15

of what they call synthetic lymphocidal chemical,

0:30:150:30:19

but which was, in fact, nitrogen mustard.

0:30:190:30:22

Because of the war, even JD's treatment was a secret.

0:30:250:30:29

They couldn't name nitrogen mustard.

0:30:290:30:32

In the records, it was simply called, Substance X.

0:30:320:30:36

X given at 4:30pm and then again,

0:30:380:30:41

X given at 9:30am the following morning.

0:30:410:30:44

He received a number of treatments using nitrogen mustard.

0:30:470:30:52

And with each one, he became a little bit better.

0:30:520:30:54

He could actually sleep at night,

0:30:540:30:56

he could swallow, he could eat, he was much more comfortable.

0:30:560:31:00

The pain became minimal

0:31:000:31:04

and he was absolutely thrilled.

0:31:040:31:05

Although not fully understood at the time,

0:31:070:31:09

nitrogen mustard works by binding to the DNA of dividing cells.

0:31:090:31:14

This triggers the cells' self-destruct mechanism.

0:31:150:31:19

Instead of dividing, the cells shut down and break apart.

0:31:190:31:23

And the cancer, hopefully, is destroyed.

0:31:230:31:26

This was the first time that a drug had been used to treat cancer.

0:31:300:31:34

This was monumental.

0:31:370:31:38

I mean, it was a huge moment in the history of medicine.

0:31:380:31:41

It is the beginnings of what we now call chemotherapy.

0:31:410:31:45

And very strange to think that it all started

0:31:450:31:48

in the horrors of the trenches of the First World War.

0:31:480:31:51

All the chemo drugs that followed

0:31:540:31:56

have had the same basic mechanism of action.

0:31:560:32:00

They are poisonous to living cells.

0:32:000:32:02

If you get the dosing right then you can kill the cancer

0:32:050:32:09

without killing the patient,

0:32:090:32:10

and in fact, nitrogen mustard is still used for

0:32:100:32:14

the treatment of some cancers.

0:32:140:32:16

But cancers are persistent.

0:32:170:32:20

Even today the prospect for people with advanced cancers is often poor.

0:32:200:32:24

For JD, treatment came too late.

0:32:250:32:28

To say that he enjoyed a few months

0:32:320:32:34

is probably accurate but ultimately he followed a downhill course.

0:32:340:32:39

JD, the world's first chemotherapy patient, survived for six months.

0:32:410:32:46

There's just one entry for the 1st of December 1942.

0:32:480:32:53

It simply says, "Died."

0:32:530:32:56

JD died peacefully,

0:32:580:33:00

unaware of the impact his life and death would have.

0:33:000:33:04

His story pulls the strings of your heart. It really does.

0:33:070:33:11

I think that he was a sad person,

0:33:120:33:17

with few friends, with a devastating disease

0:33:170:33:21

and he made a huge contribution to management of cancer.

0:33:210:33:26

So we are grateful to him for that,

0:33:270:33:30

and we share his agony at the same time.

0:33:300:33:34

The field of chemotherapy,

0:33:440:33:46

and indeed the very idea of using poisons as medicines,

0:33:460:33:50

poses fundamental questions about toxicity.

0:33:500:33:53

How do you decide which substances are poisonous and which are not?

0:33:540:33:58

After all, even the ancients realised

0:34:000:34:02

that poisonous is a relative term.

0:34:020:34:05

"All substances are poisonous. There is none that is not poisonous."

0:34:060:34:11

Now, that's according to 16th century doctor

0:34:110:34:14

and chemist, Paracelsus.

0:34:140:34:17

He goes on to add, "If it's simply the dose which determines

0:34:170:34:20

"whether a substance is poisonous or not."

0:34:200:34:24

Even water can be lethal if you drink enough of it.

0:34:250:34:29

Too much causes brain cells to swell,

0:34:290:34:31

which can lead to coma and death.

0:34:310:34:33

So how much water would I have to drink for it to kill me?

0:34:360:34:40

About seven litres drunk over a few hours,

0:34:400:34:43

that would leave me with a 50/50 chance of surviving,

0:34:430:34:45

and when it comes to coffee, about 100 would probably finish me off.

0:34:450:34:51

And it's not just the amount that matters,

0:34:520:34:55

the toxicity of a substance can depend on what species you are.

0:34:550:34:59

Now, I absolutely love chocolate. If I were to eat a bar this big

0:35:010:35:06

then it would probably make me feel a little bit queasy

0:35:060:35:09

but nothing worse.

0:35:090:35:10

However, it would be a very different story

0:35:100:35:12

if I was a dog like Dolly here.

0:35:120:35:14

Because chocolate is very bad for dogs.

0:35:140:35:17

Two bars this size on a dog this size, could well be lethal.

0:35:170:35:22

The thing is it contains a substance called theobromine.

0:35:220:35:26

And theobromine in dogs causes vomiting,

0:35:260:35:30

heart problems, and convulsions.

0:35:300:35:32

So this is for me and not for you.

0:35:320:35:35

Toxicity also varies according to the type of exposure.

0:35:380:35:41

Whether the poison just touches the skin or is inhaled,

0:35:410:35:44

ingested or even injected.

0:35:440:35:47

Nonetheless, it is extremely useful to have a comparative scale

0:35:490:35:53

of how toxic various substances are.

0:35:530:35:55

One measurable lethality is the LD50,

0:35:570:36:00

the lethal dose 50%.

0:36:000:36:02

In other words, how much of a substance

0:36:020:36:05

would kill half of these mice?

0:36:050:36:07

Although now rarely tested on rodents,

0:36:070:36:11

the concept of LD50 has stuck.

0:36:110:36:14

To allow for size, doses are given per kilogram of body mass.

0:36:140:36:20

On a standardised LD50 scale,

0:36:210:36:24

water comes in at greater than 90,000 milligrams

0:36:240:36:26

per kilogram of body mass.

0:36:260:36:29

Pure alcohol is fatal to half the population

0:36:290:36:33

at 7,000 milligrams per kilogram.

0:36:330:36:36

While caffeine weighs in at 192.

0:36:360:36:39

Arsenic has an LD50 of 14, curare is lethal at only 0.5.

0:36:400:36:47

So while anything can be poisonous,

0:36:490:36:51

substances with an LD50 less than 100 milligrams per kilogram

0:36:510:36:55

tend to be called poisons.

0:36:550:36:58

On this scale most chemotherapy agents, including nitrogen mustard,

0:36:590:37:03

would register between one and four milligrams per kilogram.

0:37:030:37:07

By the 1950s, researchers had turned some poisons

0:37:120:37:15

into effective drugs.

0:37:150:37:18

Natural plant poisons like curare were being used in surgery,

0:37:180:37:22

and synthetics like nitrogen mustard,

0:37:230:37:26

were having an impact on cancer.

0:37:260:37:28

They were just a small part of a new enthusiasm

0:37:300:37:33

for pharmaceutical products.

0:37:330:37:36

But in this dash for cash, the authorities overlooked the fact

0:37:360:37:40

that while poisons can be medicines, medicines can also be poisons.

0:37:400:37:45

It was only a matter of time before something went badly wrong.

0:37:470:37:52

Amongst those rushing out new drugs, was a German company

0:38:010:38:04

called Chemi Grunenthal.

0:38:040:38:06

Staffed by many former Nazis,

0:38:080:38:10

they were searching for lucrative new medicines

0:38:100:38:13

and had created a chemical

0:38:130:38:15

that looked particularly interesting.

0:38:150:38:17

Structurally, the drug was very similar to barbiturates,

0:38:180:38:22

a class of drug that was then widely being used

0:38:220:38:24

by anyone who had a sleep disorder.

0:38:240:38:27

So the company decided to send it off to doctors

0:38:270:38:29

and get them to try it on their patients who had sleeping problems.

0:38:290:38:34

The new drug did well, and was soon being heavily marketed

0:38:340:38:38

as effective against insomnia, coughs, colds and headaches.

0:38:380:38:43

Oddly enough, it was a sedative

0:38:430:38:45

but it was also known to be quite useful in morning sickness

0:38:450:38:49

for pregnant women.

0:38:490:38:51

It was distributed initially

0:38:510:38:54

under the brand name Distaval.

0:38:540:38:56

By 1960, Distaval was sold throughout Europe,

0:38:590:39:02

South America, Africa, Canada and Australia.

0:39:020:39:05

Around this time the number of babies being born

0:39:100:39:13

with deformed or missing limbs and organs,

0:39:130:39:16

well, they started to rise.

0:39:160:39:18

Initially just a few, but then the numbers took off.

0:39:180:39:21

Now this was clearly really distressing,

0:39:210:39:24

and something was going on. The problem was, the doctors

0:39:240:39:27

didn't have a clue what.

0:39:270:39:30

Several traumatic years passed before the cause was finally found,

0:39:310:39:36

when a young Australian doctor

0:39:360:39:37

looked at the mothers rather than the babies.

0:39:370:39:40

The only thing he could find was that these women had all suffered

0:39:410:39:45

from morning sickness in their early months of their pregnancy.

0:39:450:39:48

And they had all been prescribed the drug Distaval,

0:39:480:39:52

which is now more commonly known by its generic name,

0:39:520:39:56

Thalidomide.

0:39:560:39:58

It has been estimated that around 10,000 babies

0:39:590:40:03

were severely disabled by Thalidomide.

0:40:030:40:06

Half of whom failed to live to adulthood.

0:40:060:40:09

The situation in America, however, was very different.

0:40:140:40:18

It was 1960, the year before the link between Thalidomide

0:40:200:40:24

and birth defects would be made.

0:40:240:40:27

Frances Kelsey was just starting out her new job

0:40:270:40:30

as the Food And Drug Administration.

0:40:300:40:33

Her first assignment was to review an application

0:40:330:40:36

to market Thalidomide.

0:40:360:40:39

Since it was already on sale in the rest of the world,

0:40:400:40:43

and since no-one yet knew that it caused birth defects,

0:40:430:40:47

it should have been a case of simply approving it.

0:40:470:40:50

But Kelsey strongly felt the application was not up to standard.

0:40:510:40:55

Here's a person who was very well trained in pharmacology,

0:40:570:41:00

and medical practice.

0:41:000:41:03

And so when she saw the application she was kind of appalled.

0:41:030:41:08

It struck her more as testimonials than good solid clinical research.

0:41:080:41:14

And she sent a letter responding to the application

0:41:140:41:17

saying that in its present form it could not be accepted

0:41:170:41:22

and to submit additional data.

0:41:220:41:25

Another application was submitted to the FDA

0:41:270:41:31

But Kelsey was still not convinced by the safety data.

0:41:310:41:35

So despite mounting pressure from the manufacturer,

0:41:350:41:38

she again refused Thalidomide a licence.

0:41:380:41:43

There was a back and forth between FDA and the mail company.

0:41:450:41:50

The mail company was getting quite annoyed, honestly,

0:41:520:41:55

threatening to go not only to the supervisor,

0:41:550:41:58

the head of the Bureau of Medicine, but the Commissioner of FDA.

0:41:580:42:02

But she stood her ground.

0:42:020:42:04

She stood her ground as a scientist,

0:42:040:42:07

she stood her ground as an FDA official

0:42:070:42:09

who of course had to uphold the law,

0:42:090:42:12

and the law required that the drug had to be safe.

0:42:120:42:15

She persevered through this whole process.

0:42:150:42:18

Kelsey continually refused to allow Thalidomide a licence.

0:42:200:42:25

When in 1961 the facts finally came out,

0:42:250:42:28

Americans appreciated just how close they had come to sharing

0:42:280:42:33

in what was by then a worldwide tragedy.

0:42:330:42:36

Frances Kelsey was given an award by John F Kennedy,

0:42:360:42:41

in recognition of her outstanding work.

0:42:410:42:45

Thalidomide was eventually withdrawn

0:42:450:42:48

from the worldwide market.

0:42:480:42:50

The fact that this tragedy was allowed to happen

0:42:500:42:53

and go on for so long, emphasises how little control many governments

0:42:530:42:58

actually had over medicines just 50 years ago.

0:42:580:43:02

In Britain, for example, the Arsenic Act,

0:43:020:43:05

and the acts that followed it, had put existing drugs

0:43:050:43:07

and chemicals under some sort of control.

0:43:070:43:10

But there was still no effective regulation

0:43:100:43:13

of newly discovered drugs.

0:43:130:43:15

After the Thalidomide scandal, new laws were passed here

0:43:160:43:20

and in other countries, which meant that in future,

0:43:200:43:23

drugs had to be safe, they had to be effective,

0:43:230:43:25

and doctors also had to tell their patients

0:43:250:43:28

if they were being given something experimental.

0:43:280:43:30

Because astonishingly enough, before then,

0:43:300:43:33

a doctor could give you pretty much what he or she wanted,

0:43:330:43:36

and they didn't have to tell you.

0:43:360:43:38

These days, pharmaceutical companies wishing to launch a new drug

0:43:380:43:42

have to go through multiple clinical trials,

0:43:420:43:45

to demonstrate that their drug is safe and effective.

0:43:450:43:49

It can take years and cost billions of pounds.

0:43:490:43:53

But it's only by doing this sort of rigorous testing

0:43:530:43:56

that you discover if a drug has significant toxic side effects.

0:43:560:44:01

The broader impact of Thalidomide,

0:44:030:44:05

it essentially creates eventually a gold standard

0:44:050:44:09

for how drugs should be evaluated.

0:44:090:44:12

Thalidomide led to much tighter regulations, which was a good thing,

0:44:120:44:17

but the story of Thalidomide does not end here.

0:44:170:44:20

Thalidomide seems to cause birth defects

0:44:210:44:24

by blocking the creation of new blood vessels.

0:44:240:44:27

Growing limbs are particularly vulnerable.

0:44:270:44:31

It is clearly a very dangerous drug.

0:44:310:44:34

Yet this notorious chemical has been found to have beneficial effects.

0:44:340:44:39

For example, when it was given to people with Leprosy,

0:44:420:44:46

their skin lesions turned from this...

0:44:460:44:48

..to this, literally overnight.

0:44:500:44:53

And it's also being successfully used

0:44:550:44:58

on a particularly hard to treat form of cancer, multiple myeloma.

0:44:580:45:02

The rise and fall and rise again of Thalidomide

0:45:040:45:06

illustrates just how tricky medical research can be.

0:45:060:45:10

In one context a drug could be a poison, in another a life-saver.

0:45:100:45:14

Despite the challenges, and with tighter regulations in place,

0:45:330:45:36

medical research continues apace.

0:45:360:45:39

While some still focus on mineral and plant poisons

0:45:400:45:44

or build synthetic ones,

0:45:440:45:45

others are now driving forward,

0:45:450:45:48

into the dangerous world of the microbe.

0:45:480:45:50

Although they are only microscopic,

0:45:530:45:55

microbes can produce toxins which are real heavyweights.

0:45:550:45:58

And the ultimate microbial poison we have purified and tamed,

0:45:590:46:03

is a toxin produced by the microbe Clostridium botulinum.

0:46:030:46:07

Botulinum toxin is the most poisonous substance known to man.

0:46:110:46:16

Now, a couple of teaspoons full would be enough to wipe out

0:46:160:46:20

every person in the UK.

0:46:200:46:23

And a couple of kilos would kill every human on the planet.

0:46:230:46:26

Fortunately, this is sugar,

0:46:290:46:31

but I do have some botulinum toxin -

0:46:310:46:33

better known as Botox - over here.

0:46:330:46:36

Only a few nanograms, but it is botulinum toxin none the less.

0:46:360:46:41

The toxin is produced by bacteria,

0:46:410:46:44

and was first discovered in poorly prepared sausages during the 18th century.

0:46:440:46:49

It was named after the Latin for sausage, botulus.

0:46:490:46:52

On the LD50 toxicity scale,

0:46:550:46:58

Botox measures just 0.000001 milligrams per kilogram.

0:46:580:47:05

The deadliest of the deadly.

0:47:070:47:10

A lethal dose for me, weighs less than one cubic millimetre of air.

0:47:100:47:15

Botulinum toxin, like curare,

0:47:160:47:19

commonly kills its victims by causing respiratory failure.

0:47:190:47:23

But unlike curare, you're not going to be able to keep someone alive

0:47:230:47:26

with a pair of bellows.

0:47:260:47:28

Because botulinum toxin lasts much longer.

0:47:280:47:31

You have to keep them on a ventilator for weeks, if not months.

0:47:310:47:35

Botox works by preventing muscles from receiving nerve signals.

0:47:370:47:43

Botox is an enzyme which enters the nerve and destroys vital proteins.

0:47:460:47:51

This stops the communication between nerves and muscles.

0:47:530:47:56

Only the growth of new nerve endings can restore muscle function,

0:47:570:48:01

and this can take months.

0:48:010:48:03

Botox is a neurotoxin, which means it destroys nerves.

0:48:060:48:10

Oddly enough, that makes it useful for a number of medical conditions

0:48:100:48:14

ranging from eye squints, to migraines,

0:48:140:48:18

from excess sweating, to leaky bladders.

0:48:180:48:22

But its main use, of course, is ironing out wrinkles in ageing faces

0:48:220:48:27

and it does this by destroying the nerves that cause frowning.

0:48:270:48:31

The quantities used are absolutely tiny,

0:48:320:48:35

a few billionths of a gram dissolved in saline.

0:48:350:48:38

In the name of science, I tried botox a few years ago.

0:48:400:48:45

-It wasn't painful, was it?

-No, no.

0:48:450:48:47

It certainly smoothed away the wrinkles.

0:48:490:48:52

But it also gave me a weird expression

0:48:520:48:55

until the new nerve endings grew back.

0:48:550:48:57

It may not be to everyone's taste,

0:49:000:49:02

but botox is certainly big business.

0:49:020:49:04

Costing around a hundred trillion pounds per kilo,

0:49:040:49:08

botox is the most expensive product on earth.

0:49:080:49:11

Huge amounts of money can clearly be made from new medicines,

0:49:270:49:31

so it's no wonder that the search for them continues.

0:49:310:49:35

Having started out by collecting exotic poisons,

0:49:350:49:38

extracted from plants, such as curare, we've come full circle.

0:49:380:49:42

As well as microscopic life, researchers are intensely

0:49:430:49:47

interested in studying some of the other ingenious killers of the natural world.

0:49:470:49:53

Killers that scuttle, slide and slither.

0:49:530:49:57

In this room there are over 250 snakes, spiders, scorpions and other venomous creatures.

0:50:050:50:12

Their venoms have evolved over millions of years

0:50:130:50:16

and they're all different.

0:50:160:50:19

The hope is that amongst this lot,

0:50:270:50:29

there are some which could lead to a significant medical breakthrough.

0:50:290:50:33

One of the greatest medical challenges is still cancer -

0:50:350:50:39

particularly, cancers of the brain.

0:50:390:50:42

Brain tumours like this one here, can be quite difficult to treat.

0:50:420:50:46

If you use radiotherapy, chemotherapy, you risk damaging healthy tissue.

0:50:460:50:52

If you can get at it and cut it out then that's good,

0:50:520:50:55

but also it's quite difficult sometimes to tell the difference

0:50:550:50:58

between tumour and healthy tissue.

0:50:580:51:01

Surgeons face a real dilemma in how much of the surrounding tissue they should remove.

0:51:040:51:09

Even though on a scan you may see a tumour,

0:51:110:51:15

that looks let's say 2cm in size,

0:51:150:51:18

we know that there are tumour cells several centimetres away

0:51:180:51:23

from that ball of tumour.

0:51:230:51:25

So to entirely remove everything you would need to be able to remove

0:51:250:51:29

all that surrounding tissue, most of which is normal brain.

0:51:290:51:32

Removing healthy brain tissue

0:51:330:51:35

could mean the difference between walking and not walking,

0:51:350:51:39

seeing and not seeing,

0:51:390:51:41

talking or being mute.

0:51:410:51:43

And so being able to pinpoint unhealthy tissue, is critical.

0:51:430:51:47

Which is where venomous animals may be able to help.

0:51:470:51:51

This is Leiurus quinquestriatus, also known as the death stalker.

0:51:530:51:58

As her name implies, she is a particularly venomous scorpion.

0:51:580:52:02

A single sting from that tail

0:52:020:52:05

could probably kill a child or an elderly person,

0:52:050:52:07

although probably not kill me,

0:52:070:52:09

it would certainly be excruciatingly painful.

0:52:090:52:13

The venom of this scorpion contains a powerful cocktail of neurotoxins,

0:52:130:52:18

chemicals that poison brain cells and nerve cells.

0:52:180:52:21

One, is called chlorotoxin.

0:52:250:52:28

Chlorotoxin affects the nervous system of insects,

0:52:300:52:33

utterly paralysing them.

0:52:330:52:35

But when trialed in human tissue,

0:52:360:52:38

it did something completely different.

0:52:380:52:41

It seemed to have a special affinity for cancer cells.

0:52:410:52:44

The compound bound to the tumour, and avidly bound -

0:52:460:52:50

in other words, once it's stuck, it stayed stuck.

0:52:500:52:53

Chlorotoxins from the scorpion venom bind tightly to receptor sites

0:52:560:53:00

on the surface of the cancer cells.

0:53:000:53:02

These are called Annexin A2.

0:53:020:53:05

Unfortunately the chlorotoxin is not strong enough to actually kill the cancer cell.

0:53:050:53:10

However, when it's mixed with a fluorescent dye,

0:53:100:53:13

it highlights cancer cells,

0:53:130:53:16

allowing surgeons to avoid cutting out healthy brain tissue.

0:53:160:53:19

It can be visually extremely difficult to differentiate tumour

0:53:220:53:27

from normal brain, they look alike they can feel alike.

0:53:270:53:31

So the ability to fluorescently identify areas that are abnormal

0:53:310:53:35

based on the fact that they bind chlorotoxin,

0:53:350:53:37

and then remove that tissue, is extremely appealing.

0:53:370:53:41

So in the operating room, we would simply switch our imaging system

0:53:410:53:46

to a system that shines infra-red light,

0:53:460:53:49

and just look at the picture we see.

0:53:490:53:52

The areas that light up blue, should be just tumour,

0:53:530:53:56

so you can detect microscopic amounts of tumour.

0:53:560:54:00

It's promising research,

0:54:010:54:02

and just one area where this venom could offer medical benefit.

0:54:020:54:06

It's been a long process and development,

0:54:080:54:10

lots of twists and turns

0:54:100:54:13

but, yeah, I'm looking forward to where the future goes with this.

0:54:130:54:17

It certainly has the potential to be very, very promising.

0:54:170:54:21

Animals produce a huge range of different venoms,

0:54:250:54:28

and many have been shown to have remarkable properties.

0:54:280:54:32

Venom from snakes has led to the production of a new type of anti-hypertensive drug,

0:54:350:54:41

for treating high blood pressure,

0:54:410:54:43

while the lethal cone snail

0:54:430:54:46

has produced one of the world's most powerful painkillers.

0:54:460:54:49

So who knows what other medicines might be lurking in the fangs of the creatures behind me?

0:54:500:54:55

Venoms are particularly appealing to modern researchers,

0:54:590:55:02

because they tend to be very specific.

0:55:020:55:05

They seek out precise targets,

0:55:050:55:08

which ties in well with another medical revolution that's going on.

0:55:080:55:12

It, too, builds on the idea of targeting -

0:55:140:55:17

but this time it's targeting at a genetic level.

0:55:170:55:21

Medicine is getting truly personal.

0:55:230:55:25

The trouble with dishing out the same drugs to everyone,

0:55:270:55:30

is that we are all different,

0:55:300:55:32

a drug that lowers my blood pressure might have absolutely no effect on yours.

0:55:320:55:37

So how close are we to creating truly personalised medicines?

0:55:370:55:41

What we've found as we've sequenced the genes of a number of people,

0:55:430:55:47

is that everybody has slight variations and subtle changes

0:55:470:55:51

in their genes,

0:55:510:55:52

and these dictate ever-so-slightly subtle differences

0:55:520:55:55

in the way that cells respond to drugs.

0:55:550:55:58

The concept is that we use that information

0:55:580:56:01

to really tailor a specific therapy for that one person.

0:56:010:56:05

We're doing it to some extent already.

0:56:100:56:13

Right now, we can sequence relevant bits of the person's cancer genome,

0:56:140:56:21

for about the same cost as many of the scans we do for patients with cancer.

0:56:210:56:25

The similar sort of cost as the pathologist looking down the microscope

0:56:250:56:29

at the slides from that person's cancer.

0:56:290:56:32

So I think it's very likely that over the next 5 to 10 years or so,

0:56:320:56:37

these kinds of genetic approaches will make their way into the clinic.

0:56:370:56:41

Personalised medicine is set to be the next big step

0:56:460:56:50

in a process that started in the early 19th century.

0:56:500:56:53

Since that time, our medical world has been utterly transformed.

0:56:560:57:00

We no longer expect to die young,

0:57:000:57:03

instead the threat comes from diseases of old age like cancer.

0:57:030:57:09

Here poisons have proved to be particularly useful.

0:57:090:57:12

Even arsenic, the murderer's friend,

0:57:130:57:15

has now found a medical use, as an anti-cancer agent.

0:57:150:57:19

Thanks to medical pioneers, we now know how to control pain,

0:57:220:57:27

infections are not the death sentence they once were.

0:57:270:57:31

And doctors use many poisons on a daily basis.

0:57:330:57:36

200 years ago, there were very few effective treatments.

0:57:440:57:47

Now, doctors are talking about targeted, specific, personalised medicines.

0:57:470:57:53

We have come a long way, but we still have a long way to go.

0:57:530:57:57

If you'd like to take part in a quiz on pain,

0:58:060:58:09

or perhaps find out something more about pus and poison,

0:58:090:58:13

then go to the website below

0:58:130:58:15

and follow links to the Open University.

0:58:150:58:18

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0:58:200:58:24

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