When venom becomes your painkiller

Author: Attabey Rodriguez-Benitez
Editors: Patricia Garay, Alison Clair Ludzki, and Noah Steinfeld.

Imagine you are not in frigid Michigan but are swimming in the warm waters of the Caribbean. The warm waters caress your skin. While you dive past a colorful reef with a plethora of fish, you see an anemone. You know you cannot touch it, because it might sting you with its toxins. Little do you know; these anemones are not the only ones capable of stinging. The reef harbors a far deadlier and more beautiful creature: cone snails. While cute on the outside, these little creatures can contain a venom cocktail of more than 100 toxins.  However, if they do sting, you will not feel any pain at all. This prompted a pivotal change in Professor Baldomero Olivera’s career. Dr. Olivero is a researcher currently at the University of Utah, where he transitioned from studying DNA synthesis to studying cone sails indigenous from his hometown in the Philippines.

Olivera received his Ph.D. in biochemistry from CalTech. His thesis work focused on DNA synthesis and enzymology. At CalTech, he discovered and characterized DNA ligase in E. coli, the enzyme responsible for joining DNA strands together during DNA replication and repair. When he was appointed at the Department of Biochemistry at the University of Philippines, he had to find a new direction for his research, as the university lacked a lot of equipment necessary to continue work in his previous field. However, he was able to leverage the unique properties of the local species of venomous cone snails to create a new field of research. It has been shown that toxins can serve as potent analgesics or painkillers, an example being tetrodotoxin isolated from pufferfish. Olivera has harnessed the potential for new drugs that cone snails may harbor without depending on cutting-edge equipment and has had a significant impact in fundamental research and medicine.

Now at the University of Utah, he separates out the components of cone snail venoms to find new drugs for use as human medicine. With more than 100 components in each venom and multiple bioactive peptides, elucidating the crucial active components can be a difficult task. In Utah, though, it is difficult to find a nearby ocean to harvest these snails. Thus, he still maintains his collaboration with the Philippines, mainly through local fishermen, to have a constant supply of these specimens. The fisherman throw their nets and leave them for 5 months to create a small ecosystem for multiple cone snail species. Over time, small ecosystems start to build up on the nets, going from bacteria, to algae and eventually to snails. The fishermen then pull up the nets and send the snails to Olivera’s research laboratory for further study. Dr. Olivera is especially interested in Colubraria reticulata, a species of cone snail more commonly known as the “blood-sucking snail” or “vampire of the Caribbean”.

Bloodsucking snails are a type of hematophagous organism: an animal that mainly gets their nutrients through the blood of their host (Figure 1). When feeding, the snails recruit molecules that act on different stages of blood clotting. These molecules can prevent blood clots by blocking fibrin polymerization. Fibrin is responsible for knitting fibers together to stop bleeding and will eventually turn into what is commonly known as a scab. Preventing the formation of the scab allows the snails to feed as long as they need. The salivary glands of these snails contain a molecule that blocks blood clot formation (Figure 1). The salivary glands of these snails also release compounds that sedate the host in order for the feeding to occur, a tactic the vampire of the Caribbean shares with other snail species Conus geographusz, and Conus tulipa. However, unlike other cone snails, the vampire snail victim is free to go home at the end of the day whereas the victims of other cone snail species are not so lucky.

These species are similar in many ways and live in the same neighborhood (ecosystem). So why does one species prefer just the blood whereas other ones prefer the happy meal? These variations between species arise due to dietary shifts in their surroundings. Even though snails live in the same reef (or apartment complex), the penthouse might not be the same as the first floor. For example, the top apartment might be hotter and get more sunlight in the summer, but be colder in the winter. Thus, the tenant might need to adapt to their surroundings. This is the case for cone snails in the reef: the top of the reef might be filled with a school of fish, but the bottom is where more vulnerable fish linger. Thus, feeding on active fish from the top might be somewhat different than feeding on lethargic fish from the bottom due to cold temperatures or resting. Scientists believe this results in the diversification of cone snail strategies to catch and feed on their prey. One strategy employed by snails that live at the top of the reef is to induce a hypnotic state in the prey by releasing nirvana cabal, an insulin-infused venom, rendering the prey as if “they are in an opium den,” says Olivera. This insulin is somewhat different from the one we are used to hearing about. The cone snail produces multiple variants of an insulin hormone, called Con-Ins G1, which is a stripped-down version of fish insulin. This simpler version has a similar effect to normal insulin, but cannot be recognized and removed by the body. Imagine that you drink coffee with a new version of caffeine that you cannot metabolize. Your body would stay perpetually caffeinated! The prey fish overdose on nirvana cabal, which results in their “hypnotic state” that cannot be counteracted.

For the vampire of the Caribbean at the bottom of the reef, the strategy is similar–but a little different. This snail uses compounds with a numbing effect to draw blood from their prey, not to hypnotize them the top-reef snails. The prey can later recover after the forceful transfusion, unlike the prey of other cone snails, like geographus and tulipa, where as soon as the prey is sedated, the fish begins to be digested. The differing methods of sedating the prey and feeding on their blood can have some advantages and disadvantages. For example, if you feed on blood you get nutrients that have already been processed—there is no need for enzymes to digest the whole fish. On the other hand, the number of fishes that drop by might be fewer than at the top of the reef. Thus, the snails need to leave the fish alive to feed on the next day.

The ingredients of the different venom cocktails of the different species of snails contain interesting molecules with unexpected bioactivity. This was the case for the patented drug Prialt, identified in the venom of the cone snail, Conus magus. This drug, also known as Ziconotide, is used when a patient suffers chronic pain and has developed tolerance to morphine and other painkillers. Colubraria reticulata venom is a great place to discover new pain relief compounds since the “numbed” state is most likely to be induced by an analgesic.

The incredible power of the array of compounds found in cone snails is evidence that nature is one of the most imaginative chemists. Even with few resources, we can tap into its potential. Creative scientists like Prof. Olivera are needed to take unconventional approaches to traditional problems, like utilizing venoms and poisons developed by cone snails as analgesics for the future. As my grandma used to say, “A falta de pan galleta,” which roughly translates to “in the absence of bread, eat a cracker”. This means that you must make the most of your situation and be resilient to obtain the best outcome. Olivera could have stayed with the arms crossed because he could not research DNA synthesis in the Philippines, but he went to look for his cracker and it was a damn good cracker.

Attabey completed her bachelor’s degree at the University of Puerto Rico, Río Piedras. Currently, she is a doctoral student in the program of Chemical Biology at the University of Michigan. After her first year she joined the labs of Prof. Alison R.H Narayan and Prof. Janet L. Smith. She focuses on using enzymes as chemical tools for the synthesis of natural products and elucidating their mechanisms of action through structural biology. In addition to research and contributing to MiSciWriters Attabey has a Spanish science blog, En Arroz y Habichuelas, where she writes about science for the general public and in Spanish! She also enjoys reading comics (Saga, Paper Girls, Bitch Planet, etc.), watching movies with a scoring above 7 on IMDB, and eating disgusting amounts of popcorn! You can follow her on Twitter and connect on LinkedIn.