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Neurotoxins Employed by Marine Organisms & Pharmaceutical Applications of Marine-Derived Chemicals

Neurotoxins are a class of over 1,000 chemicals that alter the structure or function of the nervous system. Biotoxins produced by marine flora and fauna are an exciting area of study as they have a number of applications to human drug development. To explore the mechanisms behind neurotoxins employed in self-defense and hunting prey, we will look at the blue-ringed octopus, lionfish, and geography cone before exploring the potential of marine toxins for drug development.

The Blue-Ringed Octopus

The blue-ringed octopus utilizes the neurotoxin tetrodotoxin in both self-defense and in hunting its prey. Generally, the blue-ringed octopus avoids confrontation: flattening its body and using camouflage to blend into its surroundings. When provoked, it uses aposematic coloration, signaling to predators it is toxic and unprofitable to attack. The octopus changes its skin from a dark yellow-brown to a bright yellow and flashes 50–60 blue rings, containing iridophores that give them a vivid and iridescent color, at a rate of three flashes per second. Darkly pigmented chromatophores beneath and surrounding these rings expand in size, creating further color contrast to discourage predators from attacking. However, if it is unable to avoid the threat, the blue-ringed octopus bites, injecting venom, containing primarily tetrodotoxin, into its victim.

The blue-ringed octopus mainly hunts crabs, shrimp, and small fish. Using its sharp beak, the octopus breaks through its prey’s exoskeleton to inject venom and paralyze its victim.

Venom is produced by symbiotic bacteria in the blue-ringed octopus’ salivary glands. It contains histamine, acetylcholine, and dopamine but primarily the neurotoxin tetrodotoxin, which is 1,200 times more toxic than cyanide.

Tetrodotoxin binds to voltage-gated sodium channels, effectively blocking the flow of sodium ions that causes neurons to fire. This damage to the nervous system leads to muscle paralysis and in severe cases, respiratory or heart failure.

How tetrodotoxin blocks sodium channels.

Lionfish

Contrary to popular belief, lionfish spines are used defensively not offensively. The sheath of the lionfish’s spine is pushed down as it pierces its victim, and venom from the glandular tissue is released into the wound.

Lionfish are ambush predators and often hunt in packs. They prey on a variety of small fish and crustaceans and even each other. Lionfish have 18 spines: 13 dorsal, 3 anal, and 2 pelvic, which they use to corner prey before swallowing them whole, never injecting their venom into prey.

Lionfish venom (acetylcholine) increases intracellular calcium, which leads to prolonged muscle contraction, a rapid release then depletion of acetylcholine, and ultimately, muscle fibrillation and loss of muscle response.

Acetylcholine binds, opening the channel and allowing diffusion of sodium (Na+) and potassium (K+) ions

Geography Cone

The geography cone hunts prey in two ways: (1) releasing toxins into the surrounding water and (2) using its needlelike tooth as a harpoon to deliver its venom directly.

  1. The geography cone uses a weaponized form of insulin, made from shorter protein chains than regular insulin, to lower the fish’s blood sugar levels and send it into hypoglycemic shock. In its lethargic state, the fish is unable to escape the cone snail.
  2. The geography cone pierces its prey with its venomous harpoon-like tooth, instantly causing paralysis.

The geography cone is the most venomous of the 500 known cone snail species, and its venom contains hundreds of different conotoxins that regulate glutamate, adrenergic, serotonin, and cholinergic pathways (neurotransmitters), sodium channels (neuronal function), and hormonal receptors and alpha-conotoxins that are similar to acetylcholine and block nicotinic receptors responsible for skeletal muscle contraction.

However, proteins isolated from cone snail venom that target specific human pain receptors could be used as painkillers up to 10,000 times more potent than morphine without its addictiveness and other adverse side effects. A synthetic version of the conotoxin (ziconotide) can be taken to treat chronic pain from cancer, HIV, and some neurological disorders.

Pharmaceutical Applications of Marine Toxins

Marine toxins like those of the blue-ringed octopus, lionfish, and geography cone are being researched for their anticancer, antiviral, antibacterial, and anti-inflammatory compounds, tumor promoters, analgesic (pain-relieving) properties, and muscle relaxants, and these so-called ‘drugs from the sea’ may be the next frontier in medicine.

Variable lymphocyte receptors (VLRs) extracted from lampreys are being investigated as treatments for brain cancer and strokes. VLRs target the extracellular matrix (ECM), extracellular macromolecules that provide structural and biochemical support for surrounding cells and facilitate communication between cells. These VLRs may be able to transport chemicals through the (usually impenetrable) blood-brain barrier and straight to the brain. If VLRs can bypass the blood-brain barrier, which blocks most drugs, they can more effectively target conditions like brain cancer and strokes than current treatment options.

In a 2010 study, eribulin, extracted from the sponge Halichondria okadai, extended the lifespan of women with breast cancer that had metastasized. Thus, it could serve as a treatment option for women with late-stage metastatic breast cancer. In that vein, chemical seriniquinone isolated from Serinicoccus, a rare genus of marine bacteria, can selectively destroy melanoma cancer cells in the laboratory and is currently being experimented on in mice models.

Trabectedin is extracted from Ecteinascidia, more commonly known as the sea squirt, and contains anti-cancer properties. It is known commercially by the brand name Yondelis and is approved to treat soft-tissue sarcoma in Russia and South Korea. Researchers are also looking to use it in combatting other forms of cancer, such as prostate and breast cancer.

Another area of study is “fish slime” or mucus that covers some species of fish to protect against pathogens in the marine environment. Researchers from California State University in Fullerton and Oregon State University in Corvallis isolated 47 distinct strains of bacteria and found five that were extremely effective against methicillin-resistant Staphylococcus aureus and three against Candida albicans.

Similarly, actinobacteria found in Laminaria ochroleuca, a species of seaweed, possesses antibacterial properties, and senior author Dr. Maria de Fátima Carvalho said, “seven of the extracts inhibited growth of breast and particularly nerve cell cancers, while having no effect on noncancer cells.”

Bridging the Gap Between the Lab and Clinic

Although the above studies show marine toxins have immense potential in combatting cancer and overcoming antibiotic-resistant strains of bacteria, there is a gap between isolated studies in the research lab and the large-scale distribution and use of drugs.

First, drugs may act differently in humans than in the culture dish since a multitude of new factors come into play. Furthermore, drugs may have harmful or unintended side effects on patients. Lastly, there may not be enough marine flora or fauna to isolate the chemicals necessary for a drug. Some species require specific, difficult-to-maintain conditions to survive, may take long periods of time to produce the necessary biotoxins, or cannot survive in captivity at all.

Although marine-derived chemicals hold great promise in medicine, it is a long, winding road to get to a place where these biotoxin derivatives will become mainstream cancer, pain-relief, and antibacterial drugs.

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Natasha Matta

Natasha Matta

Interested in all things health equity, social justice, and empowerment.