Botulinum Toxin

botulinum-toxin

 

In 1981, a radical new treatment saw the use of a toxin produced by the Clostridium botulinum bacterium to treat strabismus (crossed-eyes). On the face of it using toxins produced by bacteria for our benefit, wouldn’t raise any eyebrows – we do it all the time in drug development. What did raise eyebrows, though, was that he was advocating the use of that specific toxin – the most dangerous of its type known to man. Indeed, a cup full of purified toxin would be enough to wipe out the entire human population. It is so deadly that around 1.5 ng (that’s a billionth of a gram) per kg of body weight is more than enough to kill you. Now, if I were to ask you if you wanted this toxin injected directly into your face, your answer would probably be no. However, that is not the case with the millions of people who have Botox treatments every year. It is this toxin – albeit tiny amounts of it – that is the key ingredient to these injections. Here, I will try to explain why this toxin is so deadly and why this is such a risky venture.

Botulinum toxins have been known since the 18th century, when the German medic Justinus Kerner (pictured) described what he thought were toxins secreted by improperly handled meat. It wasn’t until the turjustinus-kernern of the 20th century that the characteristics of the toxin as we know them today were discovered. Edwin van Ermengem, a
Belgium microbiologist, found that the toxin in the blood of a patient actually came from a rod-shaped bacterium – Clostridium botulinum. This bacterium thrives in poorly handled meat, secreting both its toxins and its spores – heat resistant, dormant forms of the bacterium that can survive and propogate even after significant ‘sterilisation’.

So how exactly does this toxin work? The bacteria produce the toxin (BTA) as a result of anaerobic respiration, so BTA is often found in sealed containers that contain no oxygen. If this toxin is ingested, it swiftly causes paralysis – first in the face, progressing through the body and finally causing death when the respiratory tract succumbs to the paralysis.

The toxin itself is made up of two chains of amino acids – a large chain and a small chain. Whilst it is synthesised in the bacteria, it is also associated with a zinc atom. The toxin isn’t fully activated until it enters the body, when the structure-of-botulinum-toxindisulphide bond (shown in purple) is cleaved.

The fully activated toxin essentially works by blocking the signals from motor neurones to our muscles, rendering them paralysed. This is all down to the inhibition of vesicle formation in motor neurones.

Vesicles are small sacs, surrounded by a membrane, that carry molecules around a cell. In neurones, these molecules are neurotransmitters, such as acetylcholine. When a signal from the brain moves down a neurone, these vesicles transport the neurotransmitters to the space between the neurone and the muscle, where they are released and can stimulate contraction of that muscle. Key to this process is the fusing of the vesicles to the neurone memebrane, so that the neurotransmitters can be effectively released.
This fusing is facilitated by SNARE proteins – these are proteins found on the surface of both the vesicle and the outer membrane of the neurone. Without these proteins, neurotransmitters cannot be released and muscles cannot contract.

It is these proteins that are directly targeted by the toxin. It degrades these proteins and leads to significant muscle paralysis across the body. This process is shown below:

botulinum-toxin-pathway

So, Botulinum toxin is a deadly toxin, capable of bringing about catastrophic paralysis. However, given that there were just 140 cases of botulism in the U.S in 2011, do we really need to be worried? Well, even if we don’t come into contact with this toxin from our food, there is a fear that this toxin could become a basis for chemical weapons.

During the Second World War, both the Allies and Germans worked extensively on weaponising Botulinum toxin. Fortunately, it was never achieved. A sobering example of how dangerous a chemical attack could be was the devastating Sarin gas attack on the Tokyo subway in 1995. So far, the only thing that has stopped a similar attack with aerosolised Botulinum toxin is the fact that it can be easily broken up by the wind. However, with many companies known to be producing Botulinum toxin illegally and some countries known to have such weapons in development, weaponised Botulinum toxin is a potential threat.

At least I’m ending on a positive note…sigh…

‘Til next time…

Joe

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