Tetrodotoxin: Why Toxic Is Complicated

(This post was written for the "Our Favorite Toxic Chemicals" blog carnival hosted by Sciencegeist.) It was a meal Captain James Cook would just as soon have forgotten. The fish, an unfamiliar species, seemed harmless enough. But after just a small taste of its liver, he and two shipmates regretted it.
"We were seized with an extraordinary weakness in all our limbs attended with a numness [sic]...We each of us took a Vomet and after that a Sweat which gave great relief. One of the pigs which had eat the entrails was found dead... When the Natives came on board and saw the fish hanging up, they immidiately [sic] gave us to understand it was by no means to be eat."
Cook had a rather more dramatic introduction to the lethal chemical tetrodotoxin than I did. I learned about it from a lecture in a windowless room. (Yes, I've linked to the original slides, still online after eight years.) That presentation had plenty to make my ears perk up. Highly poisonous. No antidote. Still kills today, because pufferfish, one of the web of creatures that makes tetrodotoxin, gets carved into a delicacy called fugu, and sometimes those knives miss a little bit of the animal's toxic innards. We weren't learning about tetrodotoxin because of its deadliness. Tetrodotoxin, to the organic chemist, is a case study. The lab where I earned my Ph.D. is in the business of making the toughest molecules it can. The lessons teams learned by forging tetrodotoxin from scratch, the idea goes, will be useful in other endeavors. Chemists for decades have argued about whether this is an appropriate way to train students, but suffice to say it's still the way that most medicinal chemists in pharma get their start. Tetrodotoxin is different things to different people. To biochemists and neurobiologists, tetrodotoxin, or TTX for short, is a tool for unraveling how pain works. Researchers today know that TTX binds to sodium channel proteins involved with pain pathways in the nervous system. To those who study the cultures of Haiti, tetrodotoxin evokes something else entirely-- the zombie of Haitian tradition. In the 1980s, ethnobotanist Wade Davis fingered tetrodotoxin as a key ingredient in a powder witch doctors use in voodoo zombie-making rituals. His doctoral thesis, as well as his bestselling book the "The Serpent and the Rainbow", about the topic eventually became the basis for a movie of the same name. Davis's results came under fire from the medical and scientific community. Another team's measurements of tetrodotoxin levels in the powder detected amounts too low to have any relevant effects, though Davis and another set of researchers have countered that fluctuations in pH dramatically affect those levels. Tetrodotoxin levels aside, "the main criticism of Wade's hypothesis is that tetrodotoxin does not confer the long term fugue that would be necessary to keep someone in a wakeful but zombified state," says Frank Swain, a science writer currently working on a book about zombies. Swain also points to clinical examinations of three purported zombies, where each was diagnosed with a mental illness. "It seems zombies are just normal people with learning difficulties, who become pawns in various feuds as one family accuses another zombifying their children," Swain says. Davis, today an explorer-in-residence at the National Geographic Society, defends his work, saying that examining zombies with a purely chemical lens ignores their cultural context. "The zombie definition in Haiti has nothing to do with the poison," he says. "Of course tetrodotoxin cannot make a zombie, but it can make someone appear to be dead." From there, the belief system takes over and makes tetrodotoxin "the obvious culprit," he adds. Whether or not you adhere to the Haitian belief system, tetrodotoxin is a chemical that's not to be messed with. Yet somehow fugu emerged as a delicacy. Customers line up, as the BBC puts it, to "play Russian roulette at the dinner table". Consuming fugu is a much bigger gamble than consuming a burger made with the infamous meat product "pink slime". But it was the slime that got the outrage. It all comes down to information and choice. According to economist Robin Hanson, America is much more paternalistic when it comes to regulating foods consumed by the poor and by children, presumably because people feel those groups are unable to obtain or act on the information they'd need to make informed food choices.

Preserved pufferfish at the Heard Natural Science Center, Fairview, Texas (Flickr/gurdonark)

With fugu, folks know what they're in for. They're aware of the risk, though they may be less aware of the black-market trade in pufferfish, or of Tokyo's recent move to ease strict regulations about who can serve it. And it doesn't end with food. Hairstylists and consumers didn't know that the cancer-causing chemical formaldehyde was in the hair-straightener Brazilian Blowout, because of the company's deceptive marketing. Now that they do, some people beg for it anyway, and drop hundreds of dollars a pop to do it. Our relationship with toxic chemicals is complicated. It isn't always Nick Kristof's "Big Chem" that's out to obscure dangers or cloud our judgement. Sometimes, it's human nature. We know smoking's bad for us, and we do it anyway. But we don't always know what lurks in, for example, a trailer provided by FEMA. Painting chemicals as "evil" or "good" is too simplistic- it's all about their doses and their context. Instead of op-eds "teaching nothing more than a generalized chemical anxiety", as Deborah Blum eloquently wrote, the world would be better served by op-eds that call for better information on what chemicals' danger thresholds are. It's a nuanced mission, but I'd venture a paper of the New York Times' caliber is up to it.

Author: Carmen Drahl

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  1. Neat post! Although I have to say I was half-expecting one of your famous hand-drawn structures. By the way, do you know why the poison is concentrated in the ovaries? I am wondering what purpose if any it serves there?

  2. Ha- this time I liked the idea of giving some love to old-school C&EN structure art. I don’t know why the poison concentrates where it does. My understanding is that it also concentrates in the liver.

  3. Utterly fascinating and an interesting looking molecule too. What a sweet irony that a medicinal chemist would start training by synthesising such a toxic compound!

  4. Thanks! And interesting point re: irony. Certainly tetrodotoxin is a useful research tool in neurobiology, and researchers have tried testing it as a treatment for cancer pain: http://www.wired.com/medtech/health/news/2003/11/61408

    What made me smile was thinking about the chemists who seem to make toxins a focus of their work, like eminent Harvard chemist Yoshito Kishi. http://www.chem.harvard.edu/research/faculty/yoshito_kishi.php Not sure I would’ve had the guts to take on that kind of project.

  5. I first read about tetrodotoxin in a Michael Palmer medical thriller called Extreme Measures. After that I found myself telling coworkers and friends about this zombie powder puffer fish poison. Its some fun words to say – tetrodotoxin, fugu, pufferfish. I would remember it thinking it rhymed with Frodo from Lord of the Rings. Remember Frodo eats fugu.

  6. Impressive that you learned of it first in a lecture. I guess you do not watch the simpsons? homer was poisoned by it early in the series.

  7. Very interesting, Carmen. Not sure I’ve told you but I worked for Kishi as an undergrad! Maybe that’s where I got my love for those huge, ridiculously complex toxin structures. Never heard the connection to zombies before!

  8. So many references to tetrodotoxin I was unaware of- thanks folks. @Explosci my Simpsons knowledge is shamefully limited, especially for the early seasons, which from what I understand are leagues better than more recent ones. And Lila, you’re a more courageous person than I. Is it true that folks had to don hazmat suits at the late stages of the palytoxin synthesis? I hope that knowledge filtered down in Kishi lab lore.

  9. The Western Oregon Roughskinned Newt also secretes tetrodotoxin through its skin. The only known death is of a guy who swallowed one on a bet. My siblings and I (and my toddler son) all played with them when we were young. They are really adorable. We’ve never figured out why we survived. Apparently being carried around in a kid’s pocket for a couple of hours is not threatening enough to cause a response.

    Wikipedia now references this source also.

    I’m working on a book on women chemists for middle schoolers and would like to correspond with you.