'Venom Doc' Tracks Down Snake Bioweapons

Venomous snakes, all of which belong to the superfamily Colubroidea, evolved glands for the storage and dispersal of their saliva approximately 60-80 million years ago. Since that time, various prey-immobilizing toxins have evolved from innocuous proteins that were normally produced in other body tissues.

Scientists believe that snakes, rather than simply tweaking proteins already expressed in their saliva, recruited and altered proteins for their chemical arsenal from other body tissues. This enabled snakes to develop more specific, highly potent toxins, ones that would cause their victims' bodies to turn against themselves upon injection. Over time, these newly derived toxins became a normal part of the saliva protein repertoire. To date, 24 different snake venom toxins have been characterized by scientists, but the evolutionary history – or tissue origin – of these proteins has not been documented.

In his March 2005 Genome Research article, Fry, the Deputy Director of the Australian Venom Research Unit, identified the origin of the 24 known snake toxin types. Surprisingly, rather than being saliva-modified proteins, 21 of the toxins were shown to have been originally derived from proteins normally expressed in other body tissues, including brain, eye, lung, heart, liver, muscle, mammary gland, ovary, and testis.

Only two of the toxins were derived from proteins presumably expressed in ancient reptile saliva. Both of these toxin types, CRISP and kallikrein, are closely related to toxins called helothermine and gilatoxin, which are produced by the Beaded Lizard and the Gila Monster, respectively.

One of the toxins in this study (called the waglerin peptide) did not exhibit any similarity to known proteins. Fry believes that it may be a reptile-specific protein.

"The wide-ranging origins of snake venom toxin - body counterparts explain the amazing diversity of ways that venomous snakes can kill their prey and why they have so much potential use in medical research," Fry explains.

Fry hopes that his findings will further research efforts focused on the use of snake toxins for therapy and treatment of diseases, including cancer, arthritis, and heart disease. "There is something peculiarly fascinating in the use of a deadly toxin as a life-saving medicine," Fry says. "The natural pharmacology that exists within animal venoms is a tremendous resource waiting to be tapped."

By comparing the amino acid sequence of each toxin to the amino acid sequences of multiple proteins from non-venomous tissues, Fry was able to reconstruct the phylogenetic history of each snake venom constituent. He determined which protein family each toxin type belonged to, and based the normal expression pattern of that protein family, he predicted from which tissue type each toxin protein had been derived.

Despite the differences in tissue origin, Fry observed that all toxins were derived from protein families with secretory function. This means that the proteins were produced in a specific tissue type and later transported out of that tissue, a necessary biochemical characteristic for saliva production in the snake venom glands.

Fry also observed that the proteins most frequently recruited and modified into toxins where those with a very stable molecular structure – those that are rich in the amino acid cysteine, which enables proteins to form intramolecular disulfide linkages. "These structures provided an excellent framework for the 60-80 million years of 'evolutionary tinkering' that have turned these proteins into potent, highly specific snake venom toxins," Fry concluded.