Of Molluscs and Men MBL Scientists Use Venom of the Cone Snail as a Tool to Study Blood Disorders

At a late 18th century auction in Europe, a determined collector raised his hand. He offered a price that no one could beat, and then took home a fist-sized object that had just outsold all other items at the auction, even a Vermeer painting. The expensive prize was a sea shell that had once belonged to a tropical marine animal known as cone snail. Nearly 100 years later, these beautiful shells are still being sought after today. Some varieties of these shells now fetch thousands of dollars at auction houses around the world.

These days cone snails are also prized for another, not so obvious asset. Hidden within the fleshy body of the beautiful snail lies a potent venom that the carnivorous creature uses to help capture its prey. It turns out that this same venom is becoming an increasingly useful tool for several areas of biomedical research, including hematology-the study of blood.

If someone had told hematologists Bruce and Barbara Furie fifteen years ago that they would be studying snail venom, they would have said "Sorry, wrong scientists," and returned to their research on hemophilia and other blood disorders. But an amino acid that is essential for healthy blood in humans has now turned up in the poisonous venom of the cone snail. That discovery interested the Furies enough to set up a year-round satellite lab at the Marine Biological Laboratory in order to learn everything they can about this important amino acid using the beautiful, but deadly, cone snail as a model.

Today the Furies divide their time between their laboratory research and clinical rounds in Boston and at the MBL, where they study the venom of the cone snail to further their understanding of how this amino acid is made, what it does, and why it exists in the first place.

Learning the hard way

In their quests to obtain beautiful souvenirs, humans probably learned the hard way about the toxic venom manufactured by the hungry cone snail. These small, slow moving animals have evolved a powerful weapon for catching their prey-and for exacting vengeance on people who grab them or stuff them in a pocket.

When the snails are close enough to their prey, most species shoot out a tiny harpoon that instantly paralyzes the prey with venom. The snail moves in, opens its flexible snout, and pulls its meal into its stomach. Cone snails come in about 500 varieties and are found mainly in the shallow waters of coral reefs in the Indo-Pacific Oceans. Of the 60 or so fish-eating cone snails, which have the most potent venom, at least two have a sting that can be fatal to humans.

The cone snail is unique among venomous animals for the complex assortment of toxins that make up its venom. The Furies have found that cone snail venom - rich in conotoxins - is an important tool in their studies on blood clotting. The tissues in our bodies can be easily damaged, but they have an effective method for repairing themselves. When a blood vessel is injured it chemically triggers a series of protein reactions in the blood. In the final step of the series, threads of a plasma protein called fibrin grow into a tangled net. A clot plugs or strengthens the damaged part of the blood vessel, allowing the healing process to begin. But this self-repairing system won't work if proteins involved in the process are missing or defective. The result of this malfunction can be any number of blood disorders, including hemophilia.

Vitamin K and blood clotting

Keeping the blood clotting mechanism functioning well begins with vitamin K. We get vitamin K naturally by eating green leafy vegetables and from the bacteria living in our intestines. Vitamin K is required for the synthesis of an amino acid- gamma-carboxyglutamic acid, or "Gla" (rhymes with blah)-that is found in certain blood clotting proteins. In humans, scientists including the Furies have shown that Gla enables a blood clotting protein to interact with the surfaces of a cell membrane, paving the way for the successful repair of damaged tissues. (In contrast, the anti-coagulant drug Coumadin works by inhibiting vitamin K's role in the synthesis of Gla.)

In other words, without vitamin K, Gla cannot be produced. Without Gla, the blood clotting protein cannot interact with the surfaces of cells. And without the successful interaction of that protein with the cell surface, blood clotting is delayed.

For the past 23 years, since its discovery in mammals, the Furies have been paying particular attention to Gla in their studies of vitamin K and blood clotting. There are other amino acids that seem like they should be able to perform the task that Gla does. "Nonetheless," says Bruce Furie, "despite its immense tool chest, nature decided it needed a new amino acid. The crucial question is, why couldn't it make do with the other amino acids?" Once scientists understood that Gla was essential for healthy blood, they found that it also appeared in proteins in a wide variety of tissues in the human body such as bone, kidney, pancreas, spleen, and lungs. The Furies and their colleagues also wanted to know which other organisms used this amino acid, and how they did so.

In 1984, ten years after Gla was discovered in human blood, Baldomero Olivera and his colleagues made "an amazing observation," says Bruce Furie. The University of Utah scientists had been isolating different cone snail conotoxins and investigating their biochemical effects on the nervous system, since the snail venom works by causing paralysis. They discovered that one particular conotoxin "contained our favorite amino acid, Gla," Furie remembers.

An evolutionary perspective

Since that discovery, the Furies have been taking an evolutionary perspective in their studies on the significance of Gla in the blood clotting process. And since setting up their laboratory at the Marine Biological Laboratory, they have been studying the architecture of cone snail peptides that containGla, down to the very last atom. They are trying to understand what role it plays in the biochemistry of both blood clotting proteins and snail venom.

The next logical question is why this particular amino acid appears in such evolutionarily distant groups as mammals and molluscs. Together with postdoctoral Fellow Eva Czerwiec, the Furies have determined that snails and humans both produce Gla by the same chemical process. They expect, therefore, that Gla must exist in animals of many other phyla. To confirm this the Furies plan to look for the genetic evidence of Gla in other species.

The Furies now keep about 15 live cone snails on hand at the MBL for their research. These beautiful but ferocious creatures are held under lock-and-key at the Marine Resources Center, where they can be kept in waters warmed to a tropical temperature. When Eva Czerwiec reaches in to the tank to retrieve one of the snails, it's obvious that in addition to the amino acid Gla, the creatures share another trait with humans, this one gustatory. The elegantly patterned cone snail attached to the side of the tank is inching slowly within reach of a smaller brown snail that with the flicker of the larger snail's deadly harpoon, will soon become a fine meal of escargot.