Sunday, September 28, 2008

Of Heroes, Maitotoxin, and Swearing Chemists

This season, the plot of Heroes revolves around averting the end of the world --again. This time, the apocalypse will be brought on by a secret formula, but what will this formula do? Thanks to some eagle-eyed chemists in Heroes' audience, we know it will probably kill the world at a cellular level with a toxin 50 times more potent than that found in blowfish.

Upon viewing the will of his late father, Hiro Nakamura can't resist peeking in his father's safe, where half of a deadly formula is hidden (clip below):

Hiro may not have paid attention in organic chem class, but some viewers did. Since I watched this on Hulu nearly a week after the premiere, I saw this comment posted to their message board on Friday by "bfrezza:" "Who needs the other half, I'd recognize that bad bear anywhere. The chemical formula that can end the world is definitely Maitotoxin." A few days earlier, "Mongpoovian" had already posted a note to the Heroes message boards pointing people to "Jacob's" blog post on the identity of the molecules as caffeine, the beginning of the synthesis of an antiviral drug like Tamiflu, and most interestingly, maitotoxin.

Maitotoxin (MTX), first isolated from a Tahitian fish known as “maito,” is produced by microscopic algae like Gambierdiscus toxicus, the organism responsible for red tide. Other than bio-polymers, like proteins and carbohydrates, which are chains of tiny, repeating subunits, MTX is the largest biological molecule known, composed of 32 fused carbon rings. It is also, gram for gram, the deadliest non-protein based toxin in the world--about 50 times more deadly than the toxin found in fugu (blowfish). Stated in another way, less than one gram of MTX would kill a half a billion mice. And while MTX has never, for obvious reasons, been tested on humans, in theory it would only less than 2.5 kilos to kill the entire population of the world,* less than the weight of one red, clay brick.

Thank goodness it's not that easy to get your hands on. Because of its complexity, a full proposal of MTX's full structure was only completed in 1998, thanks to the efforts of several teams of scientists at Harvard and, appropriately for the plot of Heroes, at Tohoku University and the University of Tokyo. Biochemists knew what atoms comprised MTX and roughly how they were arranged. However, just as the same make and model of car can have its steering wheel and gas tank on the right or the left, the "stereochemistry" of MTX--whether the atoms branching off of each carbon vertex pointed to the left or right --had yet to be determined for each vertex.

Why is stereochemistry important? In the case of a car, there are just 22, or four possible configurations of a car's steering wheel and gas tank. If you drove up to the right side of the pump island at a gas station, your configuration would make the difference between whether you would need to walk around to the other side of the car, or get back in your car and pull around to the other side. With chemistry, the three-dimensional structure of a molecule like a hormone, neurotransmitter or drug determines whether it can dock onto cells and have an effect--to make you grow, to help you retrieve the name of your grand-aunt, or to kill you. In the case of MTX, there were about one hundred, left-right decisions, or one nonillion possibilities (that's ten commas, folks).

Those are also the nonillion reasons why this is a daunting molecule to synthesize from scratch, but one lab is attempting to scale this Everest. Last October, K.C. Nicolaou published a paper showing that he and his colleagues at Scripps Institute in La Jolla had synthesized five the of the 32 rings of MTX. This February, that increased to nine rings. This is stirring some controversy among the synthetic chemistry community, but not for the reasons you might think--they simply debate whether Nicolaou's synthesis is meaningful beyond the sheer challenge of it (the bulletin board is worth a look if only to see how scientists, or at least graduate students, write outside of academic papers; one writes "What surprises me is that they can crystallize fckn huge 100s kDa proteins and can’t get MTX crystal!" Another says, "Ahhh… the wonders of Grubb’s catalyst. I usually run my shit on an MPLC, really slowly, a few times.") This synthesis work is intended simply to verify the structure of MTX, but one could see how in the hands of a sci-fi writer, the completion of this work could bring about worldwide disaster. As biological warfare agents go though, there are certainly enough sufficiently deadly toxins in the world that would be much easier to produce.

That being said, the Heroes staff has taken a few liberties--a careful look at the screen below shows that this is not exactly MTX. Below, I compare a drawing from Heroes with that of MTX. Whether intentionally or not, the production designers introduced some differences in structure (circled in red are substitutions of alcohols for hydrogens, and vice versa).

Images from Heroes, Season Three, Episode One on NBC and Nicolaou. ACIEE, 2006, Early View. DOI: 10.1002/anie.200604656.

They also have not copied the stereochemistry notation exactly. You'll notice that in the image below, the chemical bonds are either depicted as lines or as dashed lines that look like railroad tracks:

These dashed lines are attempts to portray three dimensions on the page; they always indicate that the bonds are receding into the page. In contrast, the proposed structure of MTX also has bonds that are shown as coming out of the page towards you, as indicated by thin, dark triangles.

Nonetheless, it's clear this fictional poison was at least inspired by MTX. Most poisoning of humans by reef fish lead to gastrointestinal distress and neurological problems similar to MS that can last for days or decades, but this is due to other toxins that G. toxicus produces and rarely results in death. MTX itself has only been tested in mice and in cell culture; there it floods cells with calcium ions, leading the cells to breakdown and rupture.

No one really knows what would happen if you gave refined MTX to a fully grown human in large quantities but no doubt the Heroes writers will show us by the end of this season.

*Estimated weight of the world population (if everyone weighed 150 lb): 490 billion kg = 7 x 109 humans x 70 kg/human

5 x 10-9 g MTX/kg human x 490 x 109 humans = 2450 g= 2.5 kg.


Anonymous said...

I am so pleased that I was not the only organic chemist who recognized a ladder polyether toxin when I saw it.

Trex said...

Ha! I'm not an organic chemist, but I am a microbiologist and phycologist and was certain that was maitotoxin when I saw it! For kicks I googled maitotoxin and heroes. I was delighted to find your post. I like the car analogy. Chemists can try to synthesize this, but in the meantime we could also try and let bacteria or fungi do it for us. Then again, unless there is a use, medical or otherwise, for this chemical then you are right, it is ethically challenging to find a good reason to do so! FYI, there are many more of these we probably don't know of being made by dinoflagellates, one of the oldest microbes still on the planet!

Copyright 2008