A deadly sea snail has evolved a unique method of hunting that uses insulin-like compounds as a biological weapon. Research reveals that the geography cone snail releases a mix of mimic molecules into the water, altering its prey’s metabolism and inducing a state of stupor. This nirvana cabal contains potent toxins, including compounds that inhibit glucagon, explaining the prey’s inability to raise blood glucose. These insights may pave the way for novel treatments for metabolic disorders and enhance imaging techniques for diagnosing cancer, showcasing the potential of these natural compounds in advancing medicine.
A snail’s pace is synonymous with slowness – but what if that snail had a head start of millions of years? A deadly sea snail has spent millennia developing metabolism-altering drugs to take down its prey, and researchers suspect that these compounds may act more rapidly and be more targeted than what human pharmacologists have created so far.
New research reveals that the geography cone snail uses a cocktail of mimic molecules to hijack its prey’s metabolism. Scientists believe that these mimic molecules could one day inspire new treatments for human metabolic disorders – and help improve imaging for certain types of cancer.
“Cone snails are good chemists,” says co-author Helena Safavi, a biomedical associate professor at the University of Copenhagen in Denmark. “They are much smarter than we give them credit for.”
A fish’s nightmare and a drugmaker’s dream
Geography cone snails are hand-sized molluscs that stalk the reefs and seafloors of the Indo-Pacific Ocean by night. We would not consider terrestrial snails very scary, but this sea snail’s attack sequence is downright nightmarish.
As the cone snail approaches a fish – which takes a fair amount of time, since they are about as fast as land snails – “the prey do not flee or swim away,” explains co-author Iris Bea Ramiro, a biochemist and postdoctoral fellow at the University of Copenhagen. Instead, the fish appear to grow drowsy and listless, floating to a stop until the cone snail shoots out its net-like mouth to envelop the fish. Then, a harpoon inside the snail’s mouth delivers a final payload of venom.
The geography cone snail’s toxins are “quite potent” and should not be taken lightly, Ramiro says. “They can kill people.”
But what explains the fish’s stupor? About a decade ago, Ramiro, Safavi and colleagues found that geography cone snails release a cloud of bioactive molecules into the water near their prey, sharply driving down the fish’s blood glucose. They dubbed the cocktail the nirvana cabal since it is “as if the fish is in an opium den,” Safavi explains.
The team found a molecule comparable to human insulin in the nirvana cabal but suspected that there was more to the cabal’s rapid and deadly results – after all, how could a snail kill a person with just a modest dose of insulin? The researchers sifted through the compounds in the nirvana cabal to search for other doppelganger molecules.
“It turns out that these mimics of human hormones are not easy to recognise – no computational tool can pick up on these very minor similarities in these short sequences” and automatically flag them, Safavi says. This meant that Ramiro had to compare the molecules they found in the nirvana cabal to the more than 300 human hormones by eye. Her meticulous study identified a suite of molecules similar to somatostatins – transmitters that might prevent the prey’s body from raising blood glucose to a healthy level.
A hidden compound
The researchers put the cone snail–produced somatostatins, or consomatins for short, through their paces to confirm their role in the nirvana cabal. Ho Yan Yeung, lead author and a molecular pharmacologist at the University of Utah Medical School, Salt Lake City, USA, tested a consomatin called pG1 on the pancreatic islets of mice – clusters of cells that contain both beta cells, which produce insulin, and alpha cells, which produce glucagon. Glucagon is the anti-insulin, signalling the body to increase blood glucose when it dips too low.
Yeung found that the consomatin suppressed glucagon production in the mice islets and whole rat pancreases – which would explain why the cone snail’s prey cannot raise their blood glucose following the insulin attack. As one final check, the researchers set out to confirm pG1’s activity in the receptors of fish. To their surprise, they found that pG1 had no effect on the cells of the cone snail’s prey species, Yeung says.
“We were really shocked,” Yeung says. “But then we thought that since pG1 is based on transcriptome prediction” – a process that uses the genetic code found in cells to estimate the shape of proteins – “we might be missing some really interesting chemical modifications”.
The researchers went back to the drawing board and analysed fresh venom samples that Ramiro painstakingly gathered from cone snails. They were astonished to find two new somatostatin-like compounds, nG1 and nG2, which had never been identified in the decades in which scientists have been studying geography snail venom. Further study revealed that nG1 and nG2 nearly perfectly mimic the somatostatins produced in fish pancreases – but since pG1 has strong activity in human cells, it may be preferred for drug development.
Why are pharmacologists interested in cone snails?
Thinking that drugmakers might want to copy a snail’s drug design homework might be surprising. But the cone snail’s “insulin and the somatostatin-like toxin we found have undergone millions of years of evolution to optimise their chemical structure – minimising it to enable the insulin-like toxin to act really rapidly,” she says. “In that sense, we can really be inspired in designing much more rapidly acting insulin.”
Regarding the somatostatins, “you can think of somatostatin as the ultimate suppressor of different kinds of hormones in our body,” Yeung says. “It has been shown that it suppresses growth hormone, insulin and glucagon – and could also suppress some immune functions.”
Human somatostatins are a somewhat blunt instrument, activating receptors all over the body and affecting several systems at once. This limits their utility for drugmakers since they are not targeted.
But the consomatins are much more specialised. “Unlike the human counterpart, we found that pG1 is really selective at only one receptor of the somatostatin receptors,” Yeung says. “This was receptor Gαo, which are densely packed in alpha cells – the pancreatic islet cells that secrete glucagon.”
This selectivity would “eliminate some unwanted side-effects of octreotide,” a drug modelled after human somatostatins currently on the market, Yeung says.
But pG1’s utility is not limited to treating people with metabolic disorders. “Many tumours, including neuroendocrine tumours, express a lot of statin receptors,” Yeudrng explains. “We think that pG1 could be a quite interesting diagnostic tool to image where these cancer cells are located.”
