Discovering the Amazing World of Venoms

Since the dawn of life on Earth, living things have faced a crucial challenge for survival: eat and do not get eaten. Predators and prey have been co-existing since the very first steps of evolution. This fact has led all life forms to undergo changes through all the history of evolution: anatomical (e.g., prickles in hedgehogs or sea urchins), behavioral (speed, alarm signals) or biochemical (bad taste). Production of toxic substances by living things appeared early in evolution, hundreds of millions of years ago. Among these substances, venoms are one of the most widespread and fascinating adaptations.

Venoms are powerful chemical cocktails that are used by venomous organisms to catch their prey and/or for defense. Venoms are normally composed of a mixture of proteins like enzymes, peptides (small proteins), and sometimes other kinds of molecules. Depending on their mode of action we can classify venoms into four types: cytotoxins that kill cells, mycotoxins that lead to muscle necrosis, neurotoxins that target the nervous system, and hemotoxins that disrupt blood clotting.

Although snakes and spiders might be the most well-known venomous animals, toxins can be found across a wide variety of organisms, including lizards, platypuses, some fish, and the main topic of this article: cone snails.

Cone Snails are Amazing Animals

Cone snails are gastropods that can be found in a variety of marine environments across tropical waters worldwide. Despite their beautiful shell patterns (Figure 1) these animals harbor a sophisticated venom apparatus (Figure 2). Like any other snail they are very slow, so they have overcome this drawback with an incredibly powerful venom that immediately paralyzes their prey. Cone snail venom consists mostly of a mixture of peptides called conotoxins, as well as other proteins and small molecules. Conotoxins act on the central nervous system, interfering with the function of nerve cells and paralyzing the prey [1]. The venom, which is contained in a duct, is injected into the prey by a muscular bulb that pumps the venom, similar to the way a syringe works.

Like many snails, cone snails also have a tooth, called the radular tooth, which is used to eat the plants they feed on. However, in cone snails, the radular tooth has been modified throughout evolution into a sophisticated device similar to a harpoon, which it injects into its prey.

Cone snails can be classified into three types depending on their feeding habits: vermivorous, which eat worms; molluscivorous, which eat molluscs; and piscivorous, which prey on fishes. Fish-hunting cone snails are the most dangerous for human beings. Why? Because the human nervous system is more like the nervous system of fishes than it is to worms or molluscs, so the venom of fish-hunting cone snails is more likely to act on the human body. There have been some cases of cone snails attacking human beings in self-defense.

Scientific Potential of Cone Snails’ Venom

If cone snails are that dangerous, how could they be useful for humans? Conotoxins have interested scientists for a long time, as potential models for developing medicines. Conotoxins have several properties that could make them good medicines. First, they are natural products created through evolution, so they have been refined for many years by nature. Second, conotoxins are not easily broken down in the body. Finally, conotoxins interact very potently and specifically with their molecular targets, which means they do not act on other molecular target so eventually they would be good candidates for developing medicines with no side effects.

In summary, hidden within cone snails, Mother Nature has created a great database of chemical weapons that specifically target the actions of nerve cells. What would happen if we could turn this to our advantage, using these toxins to treat diseases in which nerve signals are not transmitted properly? If we find the correct dose, we might be able to change the activity of nerve cells and therefore treat these diseases.

At this time, there is only one approved drug developed from conotoxins. This drug, called ziconotide, was developed from a conotoxin isolated from the venom of the cone snail Pionoconus magus (Figure 3). The painkilling effect of ziconotide is 1,000 times more potent than even morphine, without the dangerous side effect of addiction that morphine has [2]. Ziconotide blocks specific “tunnels” through the cell membrane, called calcium ion channels, that are involved in nerve cell function. By reducing the signals nerves send, ziconotide causes patients to feel less pain.

Some drugs derived from the components of venoms are used to treat some very common diseases, like high blood pressure. A drug called captopril, one of the top-selling blood pressure medicines, was developed from a peptide found in the venom of the snake Bothrops jararaca.

Exenatide is another good example of the successful use of venoms to develop drugs. Exenatide is used to treat diabetes and was developed from a peptide identified in the venom of the Gila monster lizard, Heloderma suspectum. It is likely that many other potential drugs are waiting hidden in the libraries that Mother Nature has built over the course of evolution.

From a Mixture of Compounds to a Drug

Venoms are complex cocktails of components that need to be characterized to figure out if they can be used as drugs. The classical characterization of natural products consists of the extraction of all components from the venom and then isolate each one from the mixture. Once isolated, scientists use laboratory methods to determine the chemical structure of each compound. This way of unraveling the complex mixtures of components present in the venom of cone snails would be extremely time consuming and require hundreds of animals. Taking that many snails from the wild would damage ecosystems. For this reason, scientists now study cone snail venom using a modern approach called integrated venomics [3], which combines several cutting-each techniques, called genomics, transcriptomics, and proteomics, to characterize conotoxins present in venom using less time and resources.

Genomics

Living organisms have a set of DNA instructions, called the genome, that controls their structure and function. Genomics studies the genome of organisms to see what genes they have, how those genes are organized, and what kinds of molecules they can produce. This information is useful because it helps scientists to understand which genes are responsible for making the different toxins in cone snail venom.

Transcriptomics

Imagine the genome as a library containing all the information needed to create an organism. Not all genes (books) are needed all the time, and the organism can choose which books (genes) it needs for each specific moment and make copies of those instructions. These copies are molecules called RNA. All the molecules of RNA present at a single moment are called the transcriptome, which is what transcriptomics studies. Transcriptomics can tell us which genes are being used at that moment and how much of each toxin the snail is producing.

Proteomics

RNA molecules are “read” by cellular machinery to create proteins. Proteins are the molecules that carry out the functions that must happen within each organism. In the case of cone snails’ venom, the proteins are the conotoxins the snail uses for predation or defense. All the protein molecules present at a given moment form what is known as proteome. Studying the proteome tells us which toxins are actually made by the snail and released in its venom. This is useful because it helps scientists focus on the toxins that really matter for hunting or defense.

Thanks to integrated venomics, we can untangle the complex mixtures that make up cone snails’ venom—but how do we test whether each compound might be useful as a potential drug? According to the most conservative estimates, there are between 100 and 200 conotoxins in each snail. There are close to 1,000 cone snail species, which means there are up to one million conotoxins! It would be almost impossible to test the activity of every one of these compounds. Therefore, we must rely on modern technologies such as artificial intelligence (AI). We can model the 3D structures of all the conotoxins present in the venom within a few minutes, thanks to an amazing new AI system called AlphaFold [4]. This and other advanced laboratory tools allow us to study the potential mode of action of each toxin in the virtual world. That way, we can screen all conotoxins present in the venom and choose those more likely to be useful for developing new drugs.

Once we choose likely drug candidates based on what we learn from AI, we can create those molecules in the lab and experiment with them, to prove what we predicted with the computer. We can even modify the molecules by adding or removing various chemical groups, to try to improve the properties that would make them good potential medicines. If they look promising, all new drugs must be approved by regulatory agencies, like the European Medicines Agency or the U.S. Food and Drug Administration, before they can be used for the betterment of humankind.

What Have we Learned from Venom?

This article has shown how science can turn something apparently harmful, such as venom, into something beneficial for humans. That should be one of the great objectives of science: to learn from the world around us to improve our quality of life. To do this, we must protect the amazing treasure we have—nature—taking all possible measures to conserve the biodiversity that surrounds us. What would have happened if Pionoconus magus would have become extinct before being studied? It would have been impossible for scientists to study its venom, and we never would have known that it contains a life-saving drug!

Glossary

Venom: ↑ Toxic secretions that are delivered into a living organism and manipulate its normal physiological functioning to the benefit of the venomous organism.

Adaptation: ↑ A heritable change in a species that improves its ability to survive and reproduce in a particular environment.

Gastropods: ↑ A vast and diverse group of more than 6,500 species of molluscs that include slugs and snails.

Conotoxins: ↑ Small proteins present in the venom of cone snail which are responsible for the activity and toxicity of the venom.

Central Nervous System: ↑ The body’s main processing center, consisting of the brain and the spinal cord.

Radular Tooth: ↑ Anatomical structure found in most molluscs used as feeding tool. Cone snails have efficiently developed it to hunt on their prey.

Integrated Venomics: ↑ Scientific discipline which includes genomics, transcriptomics, proteomics and metabolomics to efficiently study the composition of venoms.

Conflict of Interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

The authors acknowledge support from Spanish Ministry of Science and Innovation (PID2022-138477NB-C21) and University of Cadiz (project sol-202400284306-tra). AF thanks to Plan Propio UCA 2024-2025 (ININV2024-004).

AI Tool Statement

The author(s) declared that generative AI was not used in the creation of this manuscript.

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