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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 work 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 importantly, it promises new drugs for cancer, heart disease
and a variety of other ills, says Bryan Fry, a snake venom expert at the
University of Melbourne in Australia. In a landmark article 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 knows 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,''
says 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 says. 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 helps
reduce blood pressure. ``This explained the ability of the snake to knock me
out so quickly,'' Fry says.
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 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 this month's 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 more deadly 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 ``re-cruited'' 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 bloodclotting 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 says.
THE WASHINGTON POST
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