Cyanobacterial neurotoxin evolved billions of years ago

This post was chosen as an Editor's Selection for ResearchBlogging.org
On the evening of June 5 in 1990, six fishermen prepared a meal of baked fish, boiled rice, boiled potatoes and boiled blue mussels that they had harvested themselves off the coast of Nantucket. An hour after finishing the meal, their mouths started to tingle. Their face, arms, legs and tongue soon went numb. These fishermen were unfortunate victims of paralytic shellfish poisoning (PSP). Two were hospitalized, but all of them recovered in the end. In more severe cases of PSP, symptoms can include a sense of throat constriction, complete loss of speech, as well as brain stem dysfunction.

The fishermen's recipe sounds nice, it really does. Fact is, the best way to enjoy mussels is alongside a plate of french fries. Trust me.

PSP is primarily caused by saxitoxin, a neurotoxin that is produced by some species of cyanobacteria and dinoflagellates. These species don’t actively secrete the saxitoxin, but produce it inside their cells. Upon their death, the poison is released from their cells.

Saxitoxin poisoning can be a major threat to marine life. Filter feeders such as krill, mussels and other shellfish that feed on the poisonous algae and bacteria can accumulate high levels of saxitoxin in their bodies. From there the saxitoxin spreads upwards through the food chain, eventually affecting sea otters, birds, fish, whales and humans. Blooms of algae and bacteria in spring and late summer can poison entire ecosystems with saxitoxin for weeks. Food authorities pay close attention to these blooms, and sometimes ban fishing in affected areas to prevent poisoned shellfish and fish from entering the markets.

Anabaena circinalis, cyanobacteria whose cells form coiled filaments, like beads on a string.

Saxitoxin is so poisonous because it blocks the sodium channels of neurons. A nerve cell relies on influxes of sodium to fire, so when the sodium channels become blocked the neuronal signalling system collapses, explaining the the numbness and paralysis that the fishermen experienced.

The biochemical production of saxitoxin is incredibly complicated, and not all cyanobacteria can do it. Just as a single sheet of paper can be transformed into a complex origami figure one fold at a time, up to thirty seperate biochemical steps lead to the transformation of a simple acetyl group into the poisonous saxitoxin. Some of these steps require highly specialized enzymes that are rarely found in other bacteria.

There are several hypotheses why the cyanobacteria go through all these efforts to produce saxitoxin. It might be obvious to conclude that saxitoxin serves as a neurotoxic chemical defense mechanism, evolved to dispense retribution on species and fishermen that (indirectly) consume these bacteria. But some research suggests saxitoxin could play a role in maintaining the acidic and osmotic balance in the bacterial cell, or in regulating the cell cycle.

Twenty-six proteins with thirty catalytic functions work together to produce saxitoxin in Cylindrospermopsis raciborskii.

A team of Australian researchers realized that the evolutionary history of saxitoxin biosynthesis could hold the key to why cyanobacteria produce saxitoxin. Murray, Mihali and Neilan therefore analyzed the ensemble of saxitoxin genes in five different strains of saxitoxin producing cyanobacteria.

They found that most genes in the saxitoxin cluster (71%) are related to genes that are regularly found in cyanobacteria. The remaining 29% have no clear analogs anywhere in the cyanobacterial family, however. These genes are related to genes found in other bacterial families, such as the gammaproteobacteria. So somewhere in history, a cyanobacterium must have acquired these genes from one of its distant cousins. Such genes seldom bring any advantages. But this time, the acquired genes complemented the cyanobacterial genes in such a way that together, they formed the instructions to produce one of the most potent neurotoxins in the world. Evolution can be strange and powerful like that.

Phylogenetic position of saxitoxin producing cyanobacteria. SxtG and SxtH are always found in the same orientation next to each other, for example. The genes in the saxitoxin cluster are organized in a similar way in different species. Figure 2 from reference.

The researchers also discovered that genes in the saxotoxin cluster tend to be placed in the same ordering and position in different species. Some genes are flipped in their orientation or have moved to a different location in the cluster, but the overall conservation of gene order (or synteny) suggests that the saxitoxin cluster had a common origin in a single ancestor.

Form the tree above, you can see that the saxotoxin cluster likely evolved in the common ancestor of a cyanobacterial group known as Nostocales (and possibly even earlier, if we consider the saxotoxin cluster in Lyngbya!). This common ancestor of Nostocales lived a whopping 2,1 billion years ago, making the saxotoxin cluster just as old. But hold on… 2,1 billion years ago there were no animals to poison. In fact, sodium channels hadn’t even evolved yet!

If chemical defense is the main purpose of saxitoxin, why would the cyanobacteria evolve to produce it, if their targets wouldn’t evolve until millions of years later? Is this a case of extreme evolutionary foresight? Unlikely. Sodium channels themselves evolved from a potassium channel. Potassium channels are standard fare in the bacterial world (unlike sodium channels), so perhaps the original target of saxitoxin was a potassium channel instead of sodium channel. Sadly, little is known about the ecophysiological role of potassium channels in bacteria, let alone what the effects of saxitoxin are.

Based on the evidence so far, I wouldn’t be surprised if saxitoxin’s toxicity is but a side effect of the larger role it plays in the cyanobacterial cell. This might be dissatisfying. When we look at the world and find something that makes us sick, it is tempting to assume that that something wants to make us sick. If we are but ‘collateral damage’ through no fault of our own, we feel insignificant and powerles. The truth is that in the eyes of cyanobacteria, who have seen two billions of years pass, who have redefined what it means to be a bacterium, who have single handedly changed the earth’s climate, we are insignificant and powerless. Something to think about, the next time I enjoy my mussels and fries.


Murray SA, Mihali TK, & Neilan BA (2010). Extraordinary conservation, gene loss and positive selection in the evolution of an ancient neurotoxin. Molecular biology and evolution PMID: 21076133


Source for picture 1, 2, 3.


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