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 Venom as a Prelude to New Drug Treatments
 
 By Rick Weiss
 
  Sixty million years after the earliest snakes figured out how to make venom in their salivary glands, descendants of the little mammals those snakes preyed on have begun to figure out just how the slithering reptiles did it.
 
 And while it is too late for those who, in the intervening epochs, found themselves hyperventilating, bleeding, paralyzed or worse as a result of a run-in with a pair of fangs, it is not too late for the rest of us.
 
 A better understanding of what snake venoms are -- and how snakes cooked them up over eons of evolution -- promises better antivenins for future snakebite victims. But more important, it promises new drugs  for cancer, heart disease and a variety of other ills, says Bryan Grieg Fry, a snake venom expert at the University of Melbourne in Australia. In a landmark article published this month, Fry traced the evolutionary roots of all the major poisons known to occur in snake venoms -- a feat that scientists said should facilitate a spectrum of biomedical discoveries.
 
 Already, venoms from snakes and other creatures have led to the development of important medications,  including the blood pressure drug captopril, which is a modified version of a toxin found in the green mamba of Africa.
 
 Venoms have also proved their mettle in basic biomedical research -- their ill effects sometimes offering the first clue that there are biological systems in the body no one knew about. A toxin found in the deadly many-banded krait of Southeast Asia, for example, led to the discovery of an entire component of the human nervous system that had been unknown.
 
 "Snakes are so inventive. Their venoms are a tremendous natural pharmacy," said Fry, who milks venom from 2,000 to 3,000 snakes a year and feels lucky to have been bitten only 24 times.
 
  One of those bites launched Fry on his quest to understand the origins of snake venoms and, with luck, discover new medical applications. The culprit was a rare Stephen's banded snake, which Fry was trying to capture in the Australian rain forest.
 
 "It knocked me out very quickly," Fry said. He collapsed in less than a minute. "As I was hitting the ground, I was thinking: 'Hmm, this is a rather unusual effect. If I survive this, I should be able to get a PhD out of it.' "
 
 He did. After recovering, he analyzed the snake's venom and found that it was loaded with especially potent "natriuretic peptides," the class of proteins that in many animals -- including humans -- naturally help reduce blood pressure. "This explained the ability of the snake to knock me out so quickly," Fry said.
 
 Fry went on to find that many snakes have versions of natriuretic toxins in their venoms, which are typically mixtures of toxins. He ended up with not only a doctorate but also a patent application for a version of the poison that may have potential as a treatment for congestive heart failure, a potentially fatal complication of high blood pressure.
 
 But the finding also made Fry wonder: How many other snake toxins are "evil twins" of molecules that are normally helpful or even necessary to life? Biologists had long speculated that some snake toxins are chemical relatives of pancreatic enzymes. The pancreas, after all, is famed for its ability to digest all kinds of biological tissues, and many snakebite wounds end up looking like errant acts of digestion.
 
 Might other toxins have similar roots?
 
 To find out, Fry did something that was relatively simple but that no one else had done before. He knew that snake toxins are proteins, and proteins are long strings of amino acids, whose order determines the protein's shape and function. He compiled the amino acid sequences for all 24 of the major known snake toxins and, with a computer program, compared them with the sequences of all the other known proteins in snakes and other backboned creatures.
 
 As reported in the March issue of the journal Genome Research, 23 of the 24 toxins were very close matches with proteins that have important functions in the bodies of vertebrates.
 
 Apparently snakes have "learned" to make these proteins in their salivary or venom glands. And not just the normal versions of those proteins but mutated versions that in many cases make them lethally more potent than the parent proteins.
 
 Some snakes, for example, make modified versions of chemicals that normally help nerve cells communicate with muscle cells -- and they do it so well they lock up the system, causing paralysis. Other snakes have "recruited" a protein that normally deactivates enzymes and altered it to deactivate an enzyme that mammals use defensively to break down one of the snake's toxins. Still other snakes produce mutated versions of blood-clotting factors that trigger countless small clots in the victims' blood. That uses up victims' own clotting factors and leads to deadly hemorrhaging.
 
 "They're throwing our natural clotting factors right back at us," Fry said.
 
 By comparing different versions of snake toxins that arose at various points in evolution, Fry was also able to get good estimates of which toxins appeared first. He has identified 10 that date to the earliest days of poisonous snakes. Contrary to previous wisdom, none of those are related to pancreatic enzymes, although at least one major toxin type eventually appeared from that source.
 
 Evolutionary studies also indicate that the first snake toxins appeared well before specialized delivery systems such as fangs, Fry said. At first venomous snakes developed grooves in their teeth to direct venom into a bite, and later they developed sophisticated venom pumps and fangs, including some that fold elegantly inside the mouth and others that remain rigid.
 
  Elazar Kochva, a zoologist who studies snake venoms at Tel Aviv University in Israel, praised the new analysis as "the first to show in such detail how many of these toxins are recruited from these other tissues." Kochva studies sarafotoxin from the burrowing asp. It is a potent mimic of the normal body hormone endothelin, which constricts blood vessels and can raise blood pressure to deadly heights.
 
 "It powerfully affects contraction of the heart. I can attest to that," Kochva said, adding, as an afterthought, "fortunately."
 
 For snake-venom researchers, every first-person story of a snakebite is a happy one.
 
   

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