After years of siege and battle, the legendary city of Troy has finally fallen, alongside the body of the greatest hero of all time. The one who slayed King Hector to avenge his loved Patroclus. The one who was never defeated in combat and was said to be the greatest warrior among the mortals. The Great Achilles, now killed by the poisonous arrow of the coward Paris. That is the mythical destiny of the biggest hero of the Trojan War, as predicted by the last breath of Hector. Some versions of the story suggest that Achilles was in fact invulnerable to any damage all over his body, with the only exception of his heel, where the dreadful projectile finally landed. Because of this, even today we use the expression “Achilles’ heel” to refer to a critical weak point of something otherwise extraordinary.
Some of the greatest advances in biotechnology have come from the discovery of the Achilles heel of some organism or undesired element. We have antibiotics that destroy bacteria; herbicides that attack undesired grasses; antitumoral drugs that are used in our endless war against cancer; and poisons that can be used against ourselves. In the case of many pests caused by animals, one of the first identified weaknesses that biochemistries were able to identify is the enzyme acetylcholinesterase. Acetylcholine is an important neurotransmitter in all animals, including insects and nematodes, and is present both in the neuromuscular joint and the central nervous system. When a cholinergic neuron is activated by any signal, it releases a burst of acetylcholine in the synapsis. That substance binds to the pertinent receptor in the next neuron, causing it to trigger action potential and continue with the neural impulse. But for this system to work properly it needs something that quickly eliminates the exceeding acetylcholine in order to stop the message. This is the work of the enzyme acetylcholinesterase. It also happens that there are many known substances that can affect the activity of this enzyme. Since they affect such key step in neuronal communication, those substances are powerful poisons that have been used to kill pests since an early stage.
The nematode Caenorhabditis elegans is currently one of the most relevant animals for biological research, even though its use as a model organism is much more recent than other heavyweights like Drosophila melanogaster, Mus musculus or Saccharomyces cerevisiae. This tiny roundworm has many advantages, such as being transparent, an hermaphrodite, being able to grow easily under laboratory conditions, a small genome and a fixed number of cells. Its curriculum also includes easy genetic manipulation, the possibility of inhibit genes in vivo at any life stage and being the first metazoan genome available. Due to its many properties it is widely used for the study of several biological processes. Thanks to its fixed cell number it also has a fixed number of neurons, making its nervous system a simple and stable model. The mapping of all the connection of all its neurons (the connectome) is known, and a considerable academic effort is put to modelize and understand every detail of its small worm brain. This system is much more tractable than human brain, but the basic biochemistry remains the same, which of course includes the role of acetylcholinesterase, for which vertebrates have two copies instead on the only one in the nematode, as you can see in our tree of the month as part of the phylome 509, C. elegans in the context of several model species. This phylome is part of the quest for orthologs initiative.
In nature, C. elegans lives in the soil, feeding on free-living bacteria and doing no harm to anybody. Unfortunately our relationship with other nematodes is not as idyllic as with our elegant friend. Many nematode species are parasites, either of animals (for instance the intestinal worm Ascaris lumbricoides or the infectious pork worm, Trichinella spiralis) or plants (with examples as the root knot nematodes of the genus Meloidogyne, that causes great damage to tomato and potato crops). Is in the last case in which we can use our knowledge of the acetylcholinesterase enzyme against them. Since plants, unlike nematodes, lack nervous system; they are not affected by those poisons. Such strategy is very dangerous, though, as the inhibitors of the acetylcholinesterase are also poisonous for many undesired targets, including the farmers and wild fauna; and for this reason the use of this type of chemicals as nematicides has been banned in many countries. However, unlike insecticides for which many alternatives are available, there are very few known substances that can be used against nematode pests, and as such there is a great concern regarding the control of these plant diseases. Alternatives are urgently needed. Alternatives that must be efficient and safe.