Poisonous snakes: Scientists identify clever antivenom cocktail

New method paves the way for mass production of snake antivenom without the many side effects of today’s products. Danish scientists – including a recipient of the Lundbeck Foundation Talent Prize – played an important role in the research and development.

Every year, around 100,000 people worldwide die from snakebites, and at least 400,000 of those who survive have to live the rest of their lives with serious after-effects. But it now seems there is hope on the horizon in the form of an improved snakebite antivenom.

This is reported in a scientific article recently published in the international research journal Nature Communications. A team of scientists from Denmark, Costa Rica and the UK are the authors of the article, and they demonstrate that it is possible to produce snakebite antivenom solely based on human antibodies. This has never been shown before.

It allows us to bypass the current production method whereby snakebite antivenom is produced by injecting doses of the poison into animals, typically horses and sheep, and then ‘harvesting’ the antivenoms produced by the animals.

“This new method has a range of advantages over the classic method,” explains Andreas Hougaard Laustsen, associate professor at DTU Bioengineering, who headed the international research team. He received the Lundbeck Foundation Talent Prize in 2017 for his work with snake antivenom.

“Snake antivenom derived from animals can cause violent reactions in humans such as anaphylactic shock, which can be fatal. But if we produce snake antivenom based on human antibodies, as we do with our method, there’s no danger of these violent reactions,” says Andreas Hougaard Laustsen.

The choice was a black mamba
To demonstrate that the new method works – and that, within a limited number of years, we will be able to avoid using horses and sheep to produce snakebite antivenom – a snake venom needed to be selected for the testing that lay ahead.

And according to Cecilie Knudsen, MSc in Molecular Biomedicine at DTU Bioengineering and one of the Danish researchers behind the project, they went all in at this point: “Because we chose to work with the black mamba, one of the world’s most dangerous snakes.”

The black mamba (Dendroaspis polylepis) lives in Africa and is a scoundrel in all respects. It typically grows to a length of 2.5 m but it can reach 4.5 m from head to tail, and with teeth measuring 3-6 mm it is able transfer up to 8 ml of venom when it bites. This might not sound like much but it is actually enough to kill around 40 people. The poison paralyses the muscles of its victims and suffocates them.

Cecilie Knudsen says that in order to give a brief outline of how snakebite antivenom is produced, using the new method based on human antibodies, it makes sense to talk about small factories:

“It’s these small factories that end up producing the antivenom – and we’ve demonstrated this in a number of laboratory trials on which the scientific article in Nature Communication is based.”

The first step of the process is to take blood from people who’ve never been bitten by a snake and then isolate the white blood cells.

DNA sequences, which code for formation of antibodies, are then extracted from these blood cells. And nature has designed each sequence to code for one specific type of antibody.

As a consequence, in the billions of DNA sequences that can be extracted from blood tests there will also be a number of sequences which are able to neutralise the potentially fatal chemical compounds found in snake venom, for instance the venom from the black mamba.

Small ‘factories’
And so, to the image of the factory – which is created when the scientists use a chemical process to insert the DNA sequences into so-called bacteriophages. Cecilie Knudsen explains:

“Bacteriophages are viruses which infect bacteria. We put one – and only one – DNA sequence into each bacteriophage and it immediately begins to produce the antibodies it’s programmed to deliver.”

It is then possible to identify in the laboratory which ‘factories’ produce antibodies to the venom being studied – in this case, the venom from the black mamba. When we know this, we can use these factories to stimulate specific production cells to mass-produce the antivenom. Without involving any horses or sheep.

But does the antivenom work?

The answer is a decisive ‘yes’ according to Cecilie Knudsen, and the scientific article explains how the antivenom was tested on mice:

“Some mice were given pure black mamba venom, which quickly killed them. Other mice were given an equivalent dose of venom as well as some of the antivenom we’ve produced using the new method. And these animals survived. The antivenom simply neutralised the snake venom, which would otherwise have been fatal.”

It will be some years before the snakebite antivenom derived according to the new method can be introduced to the market. The research team will also attempt to produce new types of antivenom that will be effective against other types of snakebite.

This will be of clear benefit in cases when victims are unsure about the type of snake that bit them.

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