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Beneath the Shell

Slow sea snails are, the unlikely inspirations for faster diabetes treatments

In the warm turquoise waters of the Philippines, a seemingly innocent cone snail crawls along the seafloor. But looks can be deceiving. No larger than a hand, with its shell a swirling mixture of whites and pinks, this sea snail is in search of sustenance. Its jelly- like body glides across the sand until it finds a resting fish. The snail has found its next victim.

The snail carefully and slowly approaches its prey. Once close enough, it stretches and opens its mouth wide. A cocktail of deadly toxins erupts from the snail’s gaping maw, coating the fish in a toxic vomit. As various toxins wash inside the fish’s gills, the fish becomes paralysed, twitching as it fights to escape - to survive. The snail approaches. The mouth opens further still as it starts to envelope its helpless prey. Slowly the fish is pulled deeper into the abyss of the snail’s stomach, until the fish is fully enveloped. The snail will then retreat back into its shell to digest the fish, whole and still alive.

The venom of a cone snail can be lethal to humans. Understandably across the Indo-Pacific, a warning is commonly given to tourists before a dive. “If it’s a cone, leave it alone”. A warning that has been ignored by Dr Helena Safavi-Hemami and her team of researchers from the University of Utah Health. They have collected these gruesome predators in the hope of improving diabetes treatments.

EM1 Picture1Coming out of its shell: A cone snail devouring its powerless prey

Diabetes mellitus, commonly referred to as diabetes, currently affects almost five million people in the United Kingdom alone. This condition can cause loss of eyesight, kidney failure and heart disease if left untreated. Diabetes comes in two forms, but both relate to complications with a crucial hormone, insulin.

Insulin helps to regulate blood sugar levels by binding to the insulin receptor of cells. This encourages the cells to take in a sugar called glucose. With cells taking in glucose, the sugar levels in the blood are reduced. Type one diabetes is a result of a body’s immune system attacking the cells in the pancreas that create insulin. Type two is a result of insufficient quantities of the hormone being produced and being unable to bind to the insulin receptors.

Every two minutes, a person is diagnosed with diabetes; the number of diabetics has doubled in the past 20 years. While there currently is no cure for this life- altering condition, diabetics can take man-made synthetic insulin injections to manage the affliction.

For Type 1 diabetes sufferers, these injections must be taken daily, but can take up to 90 minutes to have an effect. Scientists are continually looking for ways to reduce this time when manufacturing the synthetic insulin taken by diabetics. Then in 2016, inspiration came from these mysterious molluscs and their paralysing venom.

In 2016, researchers lead by Dr Safavi-Hemami identified that one species of fish-eating cone snail, Conus geographus, had insulin in its venom. The insulin is used to rapidly decrease the blood sugar of its prey - paralysing its victim. However, the cone snail’s insulin had a different structure to that found in humans. “Every now and then, we learn something unique from nature and millions of years of evolution.”

EM 2 cone snailHuman insulin contains two regions, A and B. The B region allows insulin to link together for storage in the pancreas, where the hormone is produced. Insulin must bind to something found in every cell called an insulin receptor, to take effect. The B region also acts like the final piece of a puzzle to fit inside and attach to the receptor. Once attached, the insulin can take effect.

The B region is copied in man-made insulin and includes the B region so it may bind to the insulin receptors. However, this same B region causes the insulin molecules to link and group in the blood once injected. It is the untangling of these molecules that causes the current delay of effect.

In 2016, it was discovered that C. geographus venom insulin lacked a B region, but could still treat diabetic symptoms in humans. The cone snail’s venom needs to be fast-acting, to instantly trap its prey, and the lack of B region ensures that the insulin does not need to be untangled. This allowed the hormone to take effect in as little as 5 minutes. While the drug did work to treat diabetic symptoms, it was shown to not be as effective as human or synthetic insulins.

With over one hundred known fish-eating cone snail species, this inspired Safavi-Hemami to examine other species. The new study published in the 12th February issue of eLife examines the insulin two other species: C. tulipa and C. kinoshitai alongside C. geographus once more.

“These snails have developed a strategy to hit and subdue their prey with up to 200 different compounds, one of which is insulin. Every now and then, we learn something unique from nature and millions of years of evolution” stated Safavi-Hemami.

All three species of sea snail had their insulin extracted from venom glands. Safavi-Hemami and her team identified seven different forms of insulin, each with a unique molecular structure. Zebrafish were exposed to a drug called streptozotocin, which created diabetic symptoms in the fish.

All seven cone snail venom insulins, that all lack a B region, were shown to bind to fish insulin receptors and lower blood glucose levels, making it likely that the venom insulins could treat diabetes in humans.

It can be said that these fish-eating cone snails are far from fussy eaters, consuming any fish small enough to be swallowed whole. This has caused cone snails to evolve a venom insulin that can work on a wide range of potential prey species. As human and fish insulin receptors are approximately 75% identical, it is hopeful that any effective cone snail insulin that works on the zebrafish will also be effective on in humans.

To discover how these venom insulins bound to insulin receptors while lacking a B region, the researchers examined how three of the venom insulins would bind to lab-grown human insulin receptors. Con-Ins G1 from C. geographus, Con-Ins K1 from C. kinoshitai, and Con-Ins T1A from C. tulipa were chosen for their higher potency.

Safavi-Hemami and her team showed that cone snail venom had structural elements which can act as a surrogate to the B region, effectively picking the lock that is the insulin receptor cell.

All seven of the discovered cone snail insulins were shown to be able to treat diabetes, but up to twenty times less effective than the currently used synthetic versions. However, these could take effect in as little as five minutes, noticeably quicker than the fastest acting currently available synthetic insulins.

“We are beginning to uncover the secrets of cone snails. We hope to use what we learn to find new approaches to treat diabetes” said Safavi-Hemami. The University of Utah Health researchers will continue to examine these venom insulins and attempt to create new synthetic insulins that combine the effectiveness of those currently available and the speed of the cone snail insulins.

It is estimated that by 2025, there will be over 5 five million people in the UK diagnosed with diabetes. As this number continues to rise, research that can improve quality of life, such as this becomes increasingly significant. A sign that some researches researchers should, in fact, not leave a cone alone. With approximately 140 other fish-eating cone snail species yet to be examined, each with their own unique venom insulins, who knows what secrets are yet to be uncovered?

The research can be found here.

Story by Christopher Bowgen

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