At a thousand times the potency of cyanide, tetrodotoxin is one of the deadliest neurotoxins in the natural world. It’s found in certain species of pufferfish and, to the right (licensed) buyer, a single fish can go for over $100. A recent study published in Angewandte Chemie outlines how, for the first time, this potent chemical has been synthesized in a lab so that it may be studied with the hope of providing a novel form of opiate-like pain relief for cancer sufferers.
Tetrodotoxin comes from bacteria like Pseudoalteromonas, Pseudomonas, and Vibrio, which live inside animal hosts. It’s been found in the organs of many marine animals including blue-ringed octopus, moon snails, ocean sunfish, and triggerfish, but perhaps the most famous example is pufferfish.
In Japan, pufferfish is hailed as a delicacy under the name fugu, even though if prepared inappropriately it can prove fatal for daring diners. Just a 1-milligram dose of tetrodotoxin is enough to kill a person, which is why chefs have to be specially trained to trim off organs such as the liver, eyes, and ovaries that are known to contain the highest quantities. There are non-toxic farmed varieties of fugu meat, but true connoisseurs covet the danger and skill involved in harvesting wild populations such as torafugu, or tiger pufferfish (Takifugu rubripes), which is the most prestigious and potentially poisonous “edible” species.
Tetrodotoxin blocks nerve impulses in the body by blocking the voltage-gated sodium channels in our cells. In doing this, it stops the brain from being able to send messages to our muscles. Eating, injecting, or inhaling tetrodotoxin can lead to paralysis, difficulty breathing, and even death. Fugu meat isn’t permitted in the EU, and in countries where it is consumed strict laws dictate who is permitted to buy and sell pufferfish products for consumption. Even with these sanctions in place, there are still cases of fugu poisoning and deaths reported each year.
In very low doses, it’s thought the nerve-blocking effects of tetrodotoxin could be used to provide effective analgesia for people suffering from severe pain, such as that caused by some treatments for cancer. The exact mechanism for this, however, is still under scrutiny, which has called for a cheap, simple, and reliable way of sourcing the potent toxin for investigation. Unfortunately for researchers, tetrodotoxin has an unusual and complex cage-like structure that makes it a tricky subject for cooking up from scratch. Smaller sections of the toxin had been synthesized in previous studies, but this new research from Yokoshima and his team is the first to achieve total synthesis.
Working at the Graduate School of Pharmaceutical Sciences at Nagoya University, Japan, the team of researchers established a novel chemical pathway for replicating the entire structure of the neurotoxin, all without the need for a trip to the aquarium. The key step to unlocking full replication was a Diels-Alder reaction between a starting compound and a silicon-containing component, which enabled the researchers to achieve a chemical structure that could attach to hydroxy groups, a vital step in recreating the neurotoxin's complex cage-like structure.
This new process for reproducing tetrodotoxin in a flask is a major step towards unlocking the properties of the powerful neurotoxin. Once an infamous delicacy in more daring sushi restaurants, pufferfish could now be at the heart of providing safe and effective pain relief to patients across the globe, so maybe it's time to leave them off the sashimi menu?
Find out what happened when a man tried mixing cocaine with pufferfish meat (NB: it's a bad idea) or check out the video below that reveals how exactly pufferfish puff.