October 21, 2023 | David F. Coppedge

Archive: Masters of Venom—Cone Snails

This CEH article from 20 years ago is reproduced for our readers’ contemplation and fascination.

Note: Some of the links within this article may no longer work.

Cone Snails: Masters of Venom    10/22/2003
Cone snails (genus Conus) are venomous molluscs living in the sea. With 500 species, they comprise “arguably the most species-rich genus of living marine invertebrates,” say a team of biologists mostly from the University of Utah, writing in a Colloquium for the Proceedings of the National Academy of Sciences1. The beautiful shells of these animals, shaped somewhat like miniature Greek urns with spiral-shaped tops, decorated with elaborate mosaic patterns reminiscent of Moorish art (see this gallery), are prized by collectors and have won them admiring names like glory-of-the-sea and cloth-of-gold.  (For more on shells, see June 26 headline.)

One wouldn’t think these little gems would be predators, but everythin’ gotta eat. Depending on the species, cone snails prey on fish, worms, and other molluscs with a unique biological weapon: protein venom. And what an arsenal they have: among the 500 species, biologists estimate they can produce 50,000 different venom peptides. (Some can even kill a human – see this website – but some of the molecules also have potential medical uses.)  Most of these are short chains of amino acids less than 100 units long; some as short as 12 to 20. These short polypeptides are produced, in turn, by enormous numbers of genes:

The analysis carried out on Conus venom peptides suggests that a majority of the estimated ~50,000 peptides are encoded by only ~12 conotoxin gene superfamilies. These superfamilies have undergone rapid amplification and divergence, accompanying the parallel radiation and diversification of Conus species at a macroevolutionary [sic] level. … Each major Conus peptide gene superfamily comprises thousands of genes, encoding different peptides. This leads to the remarkable functional diversity seen among the ~50,000 different peptides.

These peptides “exert a powerful effect on some specific ion channel or receptor target” in their prey. The sheer number of peptides these animals can manufacture is staggering. The authors put it in perspective:

It is fair to say that the snails likely have evolved a greater diversity of ion channel-targeted pharmacological agents than even the largest of pharmaceutical companies (this diverse array includes peptides that are being developed for use as human pharmaceuticals). These venom peptides have allowed different cone snail species to specialize on at least five different phyla of prey and defend themselves against a spectrum of predators that might be even more diverse.

Following this awe-inspiring introduction, the authors delve into the biochemical details of the venoms of just two species, and then make some generalizations about their putative evolution.

Most proteins and enzymes are longer than 100 amino acid units, probably because they must be that long or longer to fold into functional three-dimensional structures. The cone snail venom peptides, though much shorter, also need to fold in a precise way. Their folds are held in place by disulfide bridges connecting cysteine residues. These cross-links must be formed between the correct cysteine residues: something needs to guide the bridges to the correct attachment points. This is the role of the PDI family of enzymes (protein disulfide isomerase). After a venom is produced by the translation machinery in the ribosome, another enzyme (gamma-Glutamyl carboxylase) modifies certain glutamate residues into gamma-carboxyglutamate, which presumably also aids the folding process. As the peptide is transferred from a reducing environment in the cytosol to an oxidizing environment in the endoplasmic reticulum (ER), folding is enhanced by PDI in the presence of doubly-ionized calcium (Ca2+). The gamma-carboxyglutamate residues, binding to the calcium, may serve as handles for the enzymes, orienting the cysteine residues in such a way that the PDI enzyme can associate them to form the correct disulfide bridges. (The authors feel what they have observed may help elucidate the more general problem of protein folding.) The final peptide is not activated until it is ejected from the venom duct, so that the venom does not jeopardize the cone snail itself.

The authors speculate about the evolutionary relationships between cone shells, insects, humans, and the common ancestors of each. Because gamma-Glutamyl carboxylase is a “highly conserved” enzyme, involved in everything from human blood clotting to Conus venom, they feel its role in protein folding was the ancestral function: “Such a folding mechanism for proteins may have been more generally important earlier in evolution, but it was probably largely supplanted later by other mechanisms for facilitating folding of larger polypeptides, such as specialized molecular chaperones.”

1Bulaj et al., “Colloquium: Efficient oxidative folding of conotoxins and the radiation of venomous cone snails,” Proceedings of the National Academy of Sciences USA, 10.1073/pnas.2335845100, published online before print Oct. 22, 2003.

These scientists did yeoman’s work with PCR and other lab techniques, but that does not qualify them as just-so storytellers. Watch them launch into Storybook Land (emphasis added):

The role of Gla [gamma-carboxyglutamate] suggested above provides an attractive general mechanism for folding small polypeptides, perhaps even including the primordial proteins. Based on structural work on signal recognition particle peptides, it was recently suggested that the first proteins evolved [sic] as membranes formed, when RNA still dominated biochemistry. Specifically, the first functional polypeptide-like chains in incipient life forms were created to deal with a membrane surrounding the catalytic/informational RNA. If this view is correct, then the possibility is raised that gamma-carboxyglutamate, with its capacity both for interacting with membranes and directing folding may have been present in the earliest functional polypeptides, which were presumably much smaller than present-day proteins. Once a Ca2+-free cytosol evolved, however, a doubly negatively charged amino acid might become a liability for intracellular protein function, and in most taxa at the present time, gamma-carboxyglutamate is probably largely a relict amino acid in a few secreted proteins. This modification remains prominent only in those present-day phylogenetic systems where more specialized uses have evolved (such as mammalian blood clotting and Conus venom peptides).

Notice how many wiggle words and evolutionary assumptions are embedded in this one paragraph.  They even twist the C word into evolutionary meaning: “life forms were created…” (in their worldview, the creator is time and chance).

All such talk is pure speculation, not science. They found no ancestry, no phylogeny, and no transitions. They connected dots miles apart with inference. Blood clotting, for example, is a tremendously complex system: so much so, that Michael Behe used it as a prime example of irreducible complexity in his book Darwin’s Black Box.  Chaperones are another hugely complex system (see May 5 headline). With a wave of the hand, they just assume chaperones came along and took over the protein-folding job at some point in deep time. They beg the question that the RNA World Scenario has any validity (see 07/11/2002 headline). So cone shells use gamma-carboxyglutamate for venom peptides, and mammals use it for blood clotting. Does that indicate a relationship?  Only if evolutionary JSS [just-so storytelling] is in your blood. (But evolutionary JSS cannot prevent theoretical hemophilia; the facts have a way of leaking out without stopping.) Evolutionary JSS is the mystical, magical, extrasensory perception (also known as imagination), that visualizes miracles in the foggy past: “…the first proteins evolved as membranes formed [a synonym for their favorite miracle word emerged], when RNA still dominated biochemistry….” This sentence demonstrates that evolutionism is a form of idolatry. Evolutionists have deities, too; they are just slower and dumber.

Evolutionists and creationists have the same facts available for study. Neither could give a complete, satisfactory, authoritative explanation for why there are so many cone snail species, and so many varieties of venom peptides and the genes that code for them, because no human observer was there when they came into existence. 500 species does not seem excessive in view of the vastness of the sea, and the variety of habitats and niches available to them. It is not beyond probability that extensive “horizontal” variation has generated much of the variety from a smaller set of original forms. Even so, no one has observed a cone snail evolving into vertebrate or any other kind of animal. All the ingredients in the cone snail – the venom ducts, the PDI enzymes, the endoplasmic reticulum, the geometric elegance of the shells, the developmental pathways, the gene superfamilies – are complex entities. The parts all work, and they all work together. Cone snails are successful in their habitats because they have what they need, and they need what they have. That’s really all that science can say about it. If evolutionists could just get off their hobby horse of connecting distant dots, both camps could agree. They could both look at cone snails, and remark with astonishment, “Well, what do you know.”

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