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The world’s most dangerous poison may be a valuable pharmaceutical

Pål Stenmark regards botulinum toxin – the world’s most dangerous poison – as a set of building blocks he can redesign and give new functions. One aim is to produce new and more effective pharmaceuticals, including pain treatments. Using molecular research, he has also found a new family of botulinum toxins, where one variant can help counteract malaria mosquitoes.

Botulinum toxins are proteins with three components: one that couples to the cell (yellow), one that makes a hole in the cell’s surface (blue), and one that is sent into the cell (red). The latter causes damage that paralyses the nerve cell. Image: Pål Stenmark

Botulinum toxin, the nerve agent commonly called botox, is best known for its miraculous effect on wrinkles. The toxin paralyses muscles in the skin so they relax. However, botox is also used for a range of medical problems, such as chronic migraines, excessive sweating and muscle cramps.

“I once visited the Astrid Lindgren Children’s Hospital to see how it is used. They were treating a girl with cerebral palsy. She had cramps in her calves that made her walk on her toes, but when they injected a little botox in her muscles they relaxed and she could walk almost normally,” says Pål Stenmark, professor of biochemistry at Stockholm University.

He has studied different botulinum toxins for over a decade, and knows this poisonous protein down to its smallest atomic detail. He regards it as if it were building blocks, which he can remodel to give new functionality and make it more useful.


Has made one of the world’s most dangerous poisons even more toxic

Pål Stenmark
Pål Stenmark’s research group has optimised a botulinum toxin, making the poison couple more effectively to the nerve cells. Photo: Rickard Kihlström

In one project he has made what is already one of the world’s most dangerous poisons even more toxic.
“Because botulinum toxins are proteins that you inject into the body, they could work just like a vaccination – the immune system can learn to recognise them. If you need large doses and repeated treatments, there is a risk you will develop an immune response that inactivates the pharmaceutical,” says Pål Stenmark.

If the immune system starts to recognise botulinum toxins, you simply become immune to the treatment and it loses its effect. To circumvent this problem, Pål Stenmark’s research group has optimised a botulinum toxin, making the poison couple more effectively to the nerve cells. This means the amount injected into the body can be reduced, so there is less risk of the immune cells discovering the protein.
“We have shown that the new toxin works better in test-tube experiments and animal trials, and now hope it will be tested in clinical trials,” says Pål Stenmark.


Working on transforming the toxin into several pharmaceuticals

His research group is also redesigning various botulinum toxins so they will function better as pharmaceutical treatments for migraines, excessive sweating and different forms of muscle cramps. They are also trying to produce toxins that affect the nerves that mediate pain, known as sensory nerves. If the toxin can paralyse the sensory nerves it will work as a painkiller.
“We enjoy rebuilding these toxins so they affect the nerve cells in many different ways,” says Pål Stenmark.

In his work, he uses X-ray crystallography and cryo-electron microscopy. These methods make it possible to obtain three-dimensional pictures of what the proteins look like. Thanks to these pictures, it is possible to map how the botulinum toxins connect to the nerve cells, and understand how they should be rebuilt to have new effects in the body.


Molecular research had an unexpected find in Japan

Pål Stenmark also found an entirely new variety of the toxin, when he was looking for molecular relatives to botulinum toxins in a gigantic gene database. Using the database, he produced a genetic family tree with all the known botulinum toxins. However, it also had a strange and conspicuous branch.
“At first, I thought something had gone wrong. But it was a bacterium that had been discovered in Japan,” says Pål Stenmark.

The bacterium came from a child who had had botulism, a disease in which botulinum toxins cause paralysis. The bacterium turned out to contain an entirely new variant of botulinum toxin, the first to be found in 50 years.


Botulinum toxin from mangrove swamps can combat malaria

Since then, this new family of botulinum toxins has expanded with another two members. Pål Stenmark found a relatively harmless variant in bacteria from cowpats, and he found a more interesting variant in partnership with American researchers who had isolated an unusual bacterium from mangrove swamps in Malaysia.
“The toxin turned out to kill malaria mosquitoes, but not other mosquitoes, which is very special. For example, it doesn’t kill Swedish mosquitoes,” says Pål Stenmark.

Researchers are now trying to understand how the poison can be so selective. The hope is that this could lead to a new pesticide for malaria mosquitoes.


How is it possible to conduct research on a lethal toxin?

But how can research be conducted on something as dangerous as botulinum toxins?
“The toxin has three components. We work on one at a time, so it’s not dangerous,” says Pål Stenmark.

It is exactly this – that it is the world’s most dangerous poison – that fascinates him:
“Russian nerve agents have nothing on this. This is the most potent toxin there is, which is what also makes it so useful as a pharmaceutical.”

Text: Ann Fernholm