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Smallpox was a terrible disease. It was often fatal, and even if you survived, you were left with scars where the painful blisters used to be.

But thanks to an aggressive eradication campaign, it became the first human disease we totally wiped out, save a few deadly samples kept in labs around the world. So far, it remains the only one we’ve gotten rid of entirely, but we’re getting close on a few more, like polio. And to do that, doctors have had to get creative, and come up with different strategies tailored to each disease.

Many diseases that are on the edge of elimination are there thanks to the same kind of preventative measures that knocked out smallpox: vaccines. But the smallpox vaccine wasn’t ideal because it involved getting people actually sick with a different but related virus to protect them. Most modern vaccines are different, and that’s in part thanks to the creativity that led to the vaccine for the bacterial infection diphtheria.

Globally, we’ve gone from hundreds of thousands of cases of diphtheria per year to less than 7,000 in 2016. Which is really awesome, because this thing is pretty nasty. The diphtheria bacteria produces a toxin which can break down tissues in the lungs and throat, forming a slimy grey mess called a pseudomembrane.

People—usually kids—were often suffocated because of it, which is why the disease became known as ‘the strangling angel’. But in the late 19th century, researchers took the toxin and injected it into healthy animals, using their immune systems to create toxin-neutralizing antibodies, which could then be injected into someone with the infection to combat it. This serum therapy proved to be pretty effective, and by 1895 companies were cranking out the antitoxin in bulk.

But this method was still a treatment, not a way to prevent new cases. So scientists attempted something pretty revolutionary. Since they could create anti-toxins, they knew that the bacterial toxin could stimulate the immune system enough that a person could theoretically create their own anti-toxins—if they survived the dose.

So they tried to find a way to inactivate the toxic effects while still retaining the toxin’s immune-stimulating abilities. And after getting the perfect mixture of formaldehyde, toxin, and heat, they did it! This deactivated toxin became known as a toxoid, and it’s the concept behind many vaccines today.

And that includes the modern version of the diphtheria vaccine. Unfortunately a few countries still lack affordable access to it. So while we’ve made lots of progress, we can’t say exactly when we’ll reach true eradication.

For a disease to be completely eradicated, there have to be literally zero cases of it in the entire world. And while smallpox is the only one to earn that title so far, arguably the next closest contender is dracunculiasis or Guinea worm disease. It’s caused by a parasitic worm that grows inside a human host—and by grows, I mean an adult female can be about a meter long.

INSIDE YOU. And back in 1986, about three and a half million people were infected with these worms. But that number dropped to only 30 cases in 2017.

Some of the last endemic countries like South Sudan are aiming to be completely guinea worm free by 2020. And that’s largely thanks to education efforts which teach people how to protect themselves. The disease gets started when the worm larvae and the tiny water fleas they develop in are ingested, usually through drinking water from still, stagnant ponds.

The young worms bust out of the stomach, find one another, and mate. Then the male dies while the female grows under the skin for 10-14 months before she very slowly starts to push towards the surface. As she does, the person usually develops a fever and painful swelling at the site of her eventual emergence.

And while it’s not quite a scene from Alien, the blister she creates as she works to break out is painful enough that people often try to soothe their wound in water—which is the exact worst thing they could do. The worm takes the opportunity to release her larvae into the water source, which starts the cycle over again. Usually these wounds occur on the legs or feet, so it can be tough to get around while they heal.

And if that’s not bad enough, they’re also prone to secondary infections, so people can be incapacitated for months if they don’t have access to good medical care. The bad news is there’s no medication to kill the worms once they’re in you. Most commonly, people wait until one starts to poke out, then grab it and twist it slowly around a stick a centimeter at a time over weeks to eventually yank the thing out.

So instead, the focus has been on educating communities how to best prevent infection and helping them get and maintain access to clean water. Surprisingly simple steps like filtering drinking water and keeping people with infections away from waters people use have gotten us to the point where the guinea worm is nearing extinction. We’ve also gotten a lot closer to getting rid of the worms behind lymphatic filariasis—but with these worms, medication is the answer.

In 2000, about 120 million people had the disease, which is a lot. But between 2000 and 2016, nearly seven billion treatments were given out, which have likely prevented or cured almost 100 million cases. About 500 million people who were once at risk aren’t anymore because more than 40 countries have made serious headway towards elimination.

And a new treatment plan received the World Health Organization’s stamp of approval in late 2017, which hopefully will help doctors stay on track to eradicate lymphatic filariasis as a public health problem by 2020. The disease gets its name from the filarial worms which cause it—little roundworms that clog the body’s lymphatic vessels. These vessels are big players in the balance and distribution of bodily fluids.

So when these worms gum up the pipes, they can cause elephantiasis, severe swelling and hardening of the limbs and genitals. An adult female worm is only about 55 millimeters long, but that’s big enough to cause blockage, and they can live for anywhere from 4 to 6 years inside you. But eradication of lymphatic filariasis really doesn’t have anything to do with destroying the adult worms.

Instead, doctors go after the babies. Antifilarials like ivermectin literally paralyze the larvae and keep them from growing up and making more baby worms. These larvae get inside people through mosquito bites.

So combine larvae-killing drugs with anti-mosquito efforts like nets and you can stop the disease in its tracks. At least, that’s the plan. There’s still plenty of work to do before these and other diseases are totally gone.

But thanks to the creative efforts of scientists and doctors throughout the years, we’re a little bit closer to thinking of them like smallpox — things of the past. Thanks for watching this episode of SciShow! If you liked learning about the history of diphtheria, you might like our episode on how sled dogs delivering anti-toxin inspired the Iditarod race. ♪.