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Thursday, June 19, 2014 - 12:45pm

To Defeat A Deadly Toxin, Disrupt Its Landing Gear

Updated: 6 months ago.
A high-resolution image of the molecular carrier that moves the botulinum toxin from the intestine into the bloodstream. The carrier (silver) creates gaps in the gut lining by grabbing the rope-like molecules (red ribbons) that tether one intestinal cell to the next.

Botulinum toxin may be the most poisonous substance on the planet. A mere speck of the stuff can kill a person.

But just what makes the toxin so potent?

Part of the answer lies in the molecules that carry the toxin through the body. These carriers, which are produced along with the toxin by the Clostridium botulinum bacterium, protect the toxin as it travels through the hostile environment of the gastroinstetinal tract, and help it bust through the intestinal wall and into the bloodstream.

Take away these carriers, and the toxin becomes 30 times less potent.

In a paper published in the latest issue of the journal Science, researchers report they have figured out the crystal structure of one of the toxin's molecular carriers. This structure helps scientists understand how the toxin is able to sneak through the lining of the intestine and into the blood.

"The whole complex looks just like the Apollo lunar module," says Rongsheng Jin, biophysicist at the University of California, Irvine and lead author on the paper. He compares the complex to the toxin's "landing gear".

This complex helps the toxin in two ways. First, as Jin implies, it lands on and then binds to the cells lining the inside of the intestine. "If they cannot stick there, [the toxin] would just go through and end up in the toilet," says Jin.

Second, and more importantly, it breaks apart the molecular tethers that bind one intestinal cell to the next, allowing the toxin to slip through the gut wall. Once in the bloodstream, the toxin attacks the motor neurons that send signals to muscle fibers, causing paralysis.

With the help of the crystal structure, Jin and his team located the precise points where the carrier grabs these molecular tethers.

They then engineered a new version of the complex, identical to the original but with these points altered.

When they gave mice a dose of the botulinum toxin paired with the original version of the complex, all 10 died. When they gave mice the same dose of the toxin, but with the slightly altered version of the complex, only 1 in 10 died.

"We gave the toxin a broken car," says Jin. "The toxin was still the toxin but it could not get to the right place."

Knowing how the botulinum toxin gets into the bloodstream is unlikely to help researchers develop new treatments for botulism anytime soon.

By the time a patient presents with botulism poisoning, the toxin is already in their blood. John Mark Carter, research chemist in the produce safety and microbiology research unit at the Department of Agriculture, says that at this point "intestinal therapy doesn't really help."

However, Jin says that understanding how these vehicles work could help scientists devise better ways to deliver drugs to the body. "We can make these proteins in the lab, assemble them into a vehicle and use them to deliver drugs to the intestine," he says.

Clearly, every toxin just needs a really sweet ride.

Copyright 2014 NPR. To see more, visit http://www.npr.org/.

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