THE defining moment of A Fish Called Wanda is when irksome Otto pops
the eponymous tropical fish into his mouth and starts chewing. Baldomero Olivera
is no movie villain but he disposes of fish with equal panache. He feeds them,
live and wriggling, to his hungry killer snails.
The snails inhabit tanks in Olivera鈥檚 laboratory at the University of Utah in
Salt Lake City. In the wild, these 鈥渃one shell鈥� snails lurk in coral reefs off
the tropical shores of the Philippines, Australia and elsewhere. All told, there
are at least five hundred species, two of them potentially lethal to humans.
Some feast on worms, others on fellow molluscs. But, as Olivera will tell you,
it鈥檚 the seventy or so fish-eating species that really know how to hunt and dine
in style.
Some extend a long, whippy tube tipped with a poisonous barb disguised as
food. Fish that swallow the bait are instantly harpooned, their fate sealed by a
dose of paralysing venom squirted through the barb. Stiff and helpless, or just
plain dead, the hapless victim, sometimes bigger than the snail itself, is
reeled into its captor鈥檚 mouth. A couple of hours later the now bloated mollusc
spits out scales and bones.
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But it is not for these reasons that Olivera gives these snails a home. Nor
is it for their colourful shells, which are highly prized by collectors (one
famously fetching more than a Vermeer painting at an auction in 1796). No,
Olivera鈥檚 abiding passion for killer snails is, in the end, down to
chemistry鈥攁nd to growing evidence that a little of what is lethal for a
tropical fish can actually do humans some good.
Most venomous creatures make do with no more than a handful of toxins. Cone
snails are more profligate: they each make hundreds if not thousands. What
Olivera and others have discovered in recent years is that these molecules are
not just active in fish. Far from it: they also lock onto proteins and receptors
in the nerves and muscles of mammals, humans included. Often with pinpoint
precision.
Hospital doctors could soon be prescribing one of these snail toxins to
people desperate for some relief from serious pain, or to protect patients鈥�
brains from damage following strokes and severe head injuries. Other snail
toxins, meanwhile, are being earmarked as potential drugs against epilepsy,
depression and schizophrenia. And though the chemical make-up of most cone snail
toxins is still unknown, drugs companies are moving in faster than wasps to jam.
A dozen or more are vying with each other to screen the venoms for new drugs, or
to buy rights to the most promising of the toxins being discovered in labs like
翱濒颈惫别谤补鈥檚.
Local and cheap
It鈥檚 a far cry from how things began in the early 1970s. Having trained and
worked as a biochemist in the US for almost a decade, Olivera found himself back
in his native Philippines without lab equipment or funds. High-tech molecular
biology was out of the question. Something local and cheap was needed instead.
As a boy, Olivera had collected seashells. He knew that some cone snails used
their venom to hunt fish, and that one of the snails, Conus geographus,
could kill people. 鈥淪o to give ourselves something to do,鈥� he says, 鈥渨e started
getting hold of these snails and testing extracts of their venoms on animals.鈥�
Their chemistry was still a mystery. 鈥淲e were pretty naive,鈥� says Olivera, 鈥渨e
thought there would be only one main lethal component.鈥�
They soon discovered otherwise. Some of the cone snail toxins isolated by
Olivera鈥檚 team worked in much the same way as the well-known cobra venom toxin.
They paralysed animals by blocking the receptors for acetylcholine through which
nerve impulses signal muscle cells to contract. Others resembled the toxin from
the Japanese fugu puffer fish. It paralyses prey by blocking the inflow
of sodium ions that muscle cells need for electrical impulses to spread and
contraction to happen. But toxins that merely paralyse animals were pretty much
old hat, and by the early 1980s, Olivera鈥攂y then back in the US鈥攚as
on the brink of abandoning cone snails.
Then his team鈥檚 luck changed. Instead of injecting toxins into the limbs of
lab mice, the researchers began injecting them into the animals鈥� brains. Weird
things happened. Some of the poisons made mice shake. Others gave them
convulsions. Still others would make newborn mice sleep but send older animals
into a tailspin of hyperactivity. Nobody had expected to see such striking and
varied effects.
Smart bombs
As the race got under way to explore the chemistry of the toxins, and
discover which receptors in the brain they were acting on, the Olivera team got
lucky again. Thanks to studies by Doju Yoshikami at the University of Utah and
Richard Tsien and his colleagues at Stanford University, it became clear that
these toxins block some of the tiny channels through the membranes of nerve
cells which periodically let in a rush of calcium ions. These calcium fluxes are
the triggers that enable nerve cells to fire. That鈥檚 why the ability to block
their channels would be a boon to the snails. The mystery was why the toxins
didn鈥檛 shut down the brains of mice completely.
The answer, when it came, was a boon to neuroscience. In the past decade, it
has become clear that mammals have not one, but at least seven different types
of calcium channel scattered through their nervous systems. It turns out that
the snail toxins which made Olivera鈥檚 mice shake block just one of these, the
N-type channels that are found widely in the spinal cord and the nerve endings
that control the behaviour of blood vessels鈥攜et are used by only certain
nerve cells of the brain. It was the toxin鈥檚 effect on this subset of brain
cells that caused the mouse tremors. The chemicals that made newborn mice sleepy
turned out to be no less pernickety. They block just one of the many types of
brain receptor that are stimulated by the neurotransmitter glutamate鈥攖he
so-called NMDA receptor.
This is the kind of clean, 鈥渟mart bomb鈥� chemical tool that anyone studying
the workings of nerve cells would kill for. By the early 1990s, cone snail
toxins were in great demand by researchers everywhere, and they still are. Other
venomous animals may secrete precision poisons, but the cone snail toxins have
another towering advantage: the midget size of their molecules. A typical snake
toxin, for example, contains around 60 to 80 amino acids strung together in a
protein chain. Some spider toxin proteins run to more than 1000 amino acids.
Cone snail toxins are mere protein fragments, their peptide chains seldom longer
than 30 amino acids or shorter than 10.
The shorter an amino-acid chain is, the easier it is to synthesise. This puts
cone snails in a league of their own. Researchers who want to study an
interesting new snail toxin can make enviable amounts it. The spider and snake
people usually have to scrape by with what can be extracted from the natural
venoms鈥攁nd 鈥渕ilking鈥� spiders is no easy task.
Such easy access to cone snail toxins means they are racing ahead in medical
research too. In clinics in the US, one of the original mouse-shaking peptides,
known as the 鈥渙mega鈥� toxin, is being injected into the spinal cords of people
dying of cancer or AIDS. The idea is to block the flow of pain impulses to the
brain in patients who no longer respond to safe doses of morphine and other
opiates. The company involved, Neurex of Menlo Park in California, may shy away
from using the term 鈥渟nail toxin鈥� for its product, especially in front of
patients. But in truth, the synthesised drug is identical to the substance found
in the venom duct of Conus magus.
Elsewhere in the US, the same peptide is being tested as a treatment for
preventing brain damage following stroke. Trials by the drugs company
Warner-Lambert suggest that injecting the drug into patients up to 24 hours
after a stroke or serious head injury reduces the damage to nervous
tissue鈥攅ven at doses low enough to avoid tremors. That fits with what is
known about the causes of such damage. When the brain is deprived of oxygen its
nerve cells suffer uncontrolled and damaging rushes of calcium. Curb those
influxes, researchers reason, and it might limit the damage.
Drastic remedy
Olivera hopes that the snail toxins which block NMDA receptors will also
prove medically useful some day, perhaps as drugs for treating epilepsy. He is
well aware, though, that scientists have always found it difficult to block
these receptors in humans without side effects such as dizziness.
And the fear of side effects means that even using the omega toxin for pain
relief remains something of a drastic remedy. If doctors did not inject the
toxin straight into the spinal cord, it would pass into the bloodstream where it
would also block N-type channels involved in the control of blood vessel
behaviour. The result would be a large drop in blood pressure. 鈥淎 person would
be unable to stand up without fainting,鈥� says Neurex鈥檚 George Miljanich, one of
the scientists behind the move to use cone snail toxins in clinics. One answer
would be to design a synthetic molecule that mimics the omega toxin but is
different enough not to cause hypotension.
Or maybe the solution can be found in the snail venom itself. 鈥淣ew molecules
are popping out all the time, with new structures and new pharmacologies,鈥� says
Paul Alewood, a peptide chemist at the University of Queensland in Brisbane, who
studies the toxins of cone snails from the Great Barrier Reef. 鈥淲e鈥檙e looking at
peptides that might not have the hypotensive effect but still work against
辫补颈苍.鈥�
Chemists reckon they have worked out the amino-acid sequence for over a
hundred different snail toxins. But even this is only scratching the surface. No
two species produce the same potpourri of toxins鈥攁nd even individual
snails vary their output, sometimes from month to month. Added to which,
researchers now suspect that there may be even more toxins in the mix than they
had thought. Counting them directly, chemists estimate that each snail produces
up to 200 at a time. But by looking instead at the snail genes that code for the
toxins鈥攐r rather, the RNA 鈥渕essages鈥� from those genes鈥擜lewood and
his colleagues conclude that there may be up to ten times as many as that.
That鈥檚 good news for chemists and drugs companies, but it does raise a
puzzle: why do these snails need so many toxins? Olivera points to the snail鈥檚
ecological predicament. 鈥淚f you have a fish flopping around at the end of your
proboscis, you鈥檒l probably attract other predators,鈥� he says. Such creatures
might steal your prey or, worse, try and eat you. Either way, says Olivera, your
best shot might be to opt for overkill.
And a larger number of snail toxins certainly makes for an awesome venom.
This year, Olivera and his colleagues showed that Conus purpurascens,
which uses the harpoon strategy, delivers a powerful one-two punch that couldn鈥檛
be matched by a single toxin. First comes an electric-eel-like shock which stuns
the fish rigid. This buys time for slower-acting toxins to spread throughout the
body, blocking the receptors and ion channels that allow nerves and muscles to
function. And even for the first punch, the snail deploys at least two toxins:
one blocks the normal movement of potassium ions out of nerve cells, the other
boosts the movement of sodium ions in the opposite direction. Together the
toxins produce a massive voltage surge, far greater than anything either one can
manage alone.
Such chemical complexity is not all good news for humans, however. It is
precisely because the venoms contain so many tiny peptide toxins that an
effective antivenin has never been found. 鈥淭hey are too numerous and too small
to stimulate the production of specific antibodies strongly,鈥� says Alewood.
Mostly this doesn鈥檛 matter. Human mishaps are rare. Neither Alewood nor Olivera,
for example, has ever been stung by a cone snail.
That said, Olivera does like to tell the tale of a certain holidaymaker in
the Philippines. Chancing upon a cone snail, and taking a shine to its shell,
the holidaymaker thought he would take it home. With nowhere better to put it,
he stowed it in the lining of his swimming trunks . . .
