Cone snails hunt with fast-acting insulin

19 March 2019

Interview with 

Helena Safavi, University of Utah

CONE-SNAIL-HUNTING

Conus geographus hunting goby fish

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Some good news for diabetes, because researchers have discovered that a family of venomous shellfish, called cone snails, use a very fast-acting insulin to immobilise their fish prey by causing the target animal’s blood sugar to plummet so it can’t swim off. A fast-acting insulin like this would be extremely useful for human diabetic patients, and now, by studying several different cone snail species, Helena Safavi and her colleagues have figured out how this insulin works, why it’s so rapid in action, and how to copy it, as she explains to Chris Smith...

Helena - Cone snails are all predatory marine snails so they prey on either worms, snails or even fish, and they’re native to the tropics so they live in beautiful areas. They have wonderful shells; there are about 800 different species and every single species has a different shell pattern and they're all very beautiful.

But we are most interested in the compounds these snails make to prey on other animals, and we've long known they produce compounds that can be used in pain relief and pain research. But what we have now found is that some of these species actually make insulin, and they release that insulin into the water that the fish is swimming in and that insulin causes blood sugar to quickly drop, and the fish that is exposed to the insulin is not able to swim away anymore.

Chris - And the cone snail snaps it up and eats it?

Helena - And once the fish is unable to swim away, the cone snail comes and can just swallow it up.

Chris - That's extraordinary to think that this thing is squirting insulin into the water. So to questions spring to mind 1) why doesn't the cone snail end up with very low blood sugar as well or doesn't insulin work in a cone snail, and 2) how does the insulin get out of the water and into the fish?

Helena - It turns out that the insulin the cone snail makes is very different to its own insulin. So the snail makes its own insulin to regulate sugar levels in its own body but the insulin that it sprays into the water is extremely similar to the insulin produced by a fish so it wouldn't be active at its own target receptor. In terms of how it gets into the fish, we think it rapidly enters the body through the gills.

Chris - The thing is though, if you did this with the kinds of insulin that we have in the clinic to give to to humans, they’re quite slow acting aren't they? Whereas a venom has to work really fast in order to immobilise a prey really fast because these things are shellfish, they wouldn't be able to pursue a fast-moving fish, so this stuff must be quick? How does it do it?

Helena - The snail has to make sure that the fish is very rapidly immobilised and the insulin acts very rapidly compared to the insulin that we make and it does that by being a single compound. Our human insulin is very sticky so an individual insulin would stick very rapidly to another insulin and to another insulin and form so-called hexamers. And the snail insulin, because it has to act very rapidly, never forms a hexamer so it can act much faster than our own insulins do.

Chris - So when our insulins go into the body do they have to unstick before they can work then, whereas what the snails are doing, is theirs never stick in the first place so they're immediately available for action?

Helena - Yes, that's exactly right. When we inject, or a diabetic patient injects insulin into the body the hexamer has to first associate into a compound that can then be active, whereas the snail never made the hexamer in the first place so it's immediately active.

Chris - Now if you know this, the obvious question to ask is well why don't we just make with our biotechnology know-how a form of human insulin which can't stick together like that?

Helena - That's a very interesting question. We have actually tried to do this for over 20 years now and we have not solved this problem because at the moment you try to make the human insulin not stick, it's not active anymore so you strip it of its activity so you can still inject it, but it won't do anything in your body anymore. Somehow the snails have solved this long-standing problem by making this insulin in its venom.

Chris -  So put me out of my misery; what has the snail been able to do that human industry over the last couple of decades couldn't? It must have discovered some kind of clever trick that we hadn't thought of?

Helena - Yes. So we think that the snail insulin binds to the human insulin receptor or the fish insulin receptor in a different fashion. It uses a slightly different surface on the receptor so the area that it uses to bind to the receptor is a little different to our human insulin, and this is how the snail has solved this.

Chris - But critically, what that means is that if you can copy what the snail does you could potentially make a human insulin that's very fast acting and not sticky in that way so when it   went into the human it would very quickly gain control of their blood sugar?

Helena - Yes, and that's exactly what we are currently trying to do, and we have made very good progress on this that we're planning to hopefully publish soon in the future. So what we’ve done is to try to learn as much as we can from the snail insulins, the different ones that we have found, and then go back to human insulin and make it non-sticky and yet active. And we have the first compound that we are hoping to put into the clinic sometime in the future.

 

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