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Radio Marinara

Interview

Station 3RRR Melbourne, Australia 102.7 FM

Transcript: Interview with Dr. Bruce Livett, 10.30 am, 7 June 1998

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Interviewer: Tim Allen

Guest: Dr. Bruce Livett, Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, Victoria, AUSTRALIA

Topic: Cone Shells and Conotoxins - Medical Applications

Week: Medical Research Week 1998


LEAD IN …… [music ] … "Angelique Kidgo there - You are listening to Radio Marinara. It is 'round about 9.30 and very soon we will be giving you the Dive Report - when we track Brett down - but before that we are going to talk to Dr. Bruce Livett from the Department of Biochemistry and Molecular Biology at the University of Melbourne.

Tim Allen: Two weeks ago the Federal Government released the Issues Paper relating to an Oceans Policy for Australia and one of the key things that was raised in that was the potential for the biopharmaceutical industry and also products from the sea .. and .. This morning we thought we would talk about one aspect of this expanding field and the study of the marine cone snail - and where it is being put to the test - so Dr. Bruce Livett is here from the Department of Biochemistry and Molecular Biology, as I said, at Melbourne University, and he joins us in the studio. Good morning Bruce.
Bruce Livett: Good Morning Tim.

Tim Allen: Bruce - Cone snails - Can you give us a little bit of a description about what a cone snail is, and do we find them in our local waters ?
Bruce Livett: Definitely - There are some in the Victorian waters. They are rather small down here - and they get larger as you go north up into the Great Barrier Reef - but the ones that you would find locally down in the rock pools at Airey's Inlet and at Lorne and under the pier [at Flinders] down at Western Port are called Conus anemone (a rather small cone about 2 cm long) and they are known as "stingers" although no one has been mutilated or killed by them, but we think that they probably have a toxic venom in them, as have the cones further north that have that have been known to kill people.

Tim Allen: Oh ! So what do they use the venom for - obviously for stinging prey I would say ?
Bruce Livett: Yes. They use it to capture their prey. Some of these shells hunt fish - and they need to immobilize the fish because a cone shell is a marine snail, and just like the garden snail that you have in your local gardens, it is rather slow moving and it needs to have all the artillery it can muster to immobilize the fish and stop it from getting away - and so it has this modified tooth (a hollow tooth that is packed full of venom) and it shoots that tooth out, it actually has the tooth loaded onto the end of like a long tongue, called a proboscis, and it puts that out, feels its prey and then jabs it (and) the modified tooth is not only hollow but it is nicely barbed, so when it goes into the prey it is secure in there and if the fish tries to swim away what it finds is that the tooth is tethered back into the mouth of the cone shell by a long filament, and the cone shell just winds it back into its mouth, usually head first, and stings it multiple times - because the cone has a number of these teeth all lined up ready to fire into it

Tim Allen: It sounds like a harpoon.
Bruce Livett: It is a harpoon. (exactly. Yeah) and if you see one under a scanning electron microscope it looks exactly like a harpoon.

Tim Allen: Now - I have read that the composition of the venom is different with every sting.
Bruce Livett: That's true! Yes. Within the venom there are about 20 different toxins and the composition of those different toxins - the relative amounts of each - vary with each sting - with each of these radula teeth - and that is fascinating in itself, but what it enables the cone shell to do is to hit different ion channels one at a time so the first time it fires it immobilizes the fish, usually by hitting the pectoral fin and immobilizing the sodium ion channel, and subsequently it fires out toxins that are rich in N-type calcium channel blockers and they act as analgesics - and so it produces first of all a rigid paralysis (of the fish) and then a flaccid paralysis, and then the cone shell is able to consume and eat by digestive means, its lovely prey.

Tim Allen: Mmm - So what kind of pharmacological properties does the venom have ?
Bruce Livett: A number of different ones - one of the most interesting is that, as I just mentioned, it has an N-type calcium channel blocker. Now what this means in practice is that analgesia is brought about by blocking N-type calcium channels and for people who are in extreme pain they are usually put onto morphine. The problem with morphine is that it becomes addictive - and so the more they get the more they need - and what happens is that they just become addicted to it and receive less and less relief from the pain, whereas with the conotoxin it is not addictive, it is between 100 -1000 times more potent than morphine as an analgesic, and so you can see the interest in this - particularly for patients who have terminal cancer or terminal AIDS where the major worry they have is not that they have cancer of AIDS - they can't do anything about that - but the neurogenic pain that is associated with that disease, and that is why they have to go onto morphine. Now there is a new treatment available using these conotoxins.

Tim Allen: That (treatment) is currently available ?
Bruce Livett: It is currently in Stage III clinical trials in the USA and is expected to get FDA approval later this year.

Tim Allen: Is this mainly the tropical cone shells that have been used for this rather than the cold water cone snails ?
Bruce Livett: It is, yes - in particular one cone shell called Conus magus, the "Cone of Magi" or The Magician's Cone". It is a tiny little cone, only about 2 cm long but it packs a wad of analgesia into its venom.

Tim Allen: Is this being artificially - or have you been able to work out the compounds and then reproduce this in the laboratory, or are you actually using natural product ?
Bruce Livett: We do both. You can use the crude venom - but you cant use that on humans of course - you need a defined compound and so the usual procedure for a biochemist is to take the venom and to purify the components from it, which are the conotoxins, and these toxins are very small proteins (small peptides with only 15 - 30 amino acids, and within that 15-30 amino acids they have 2 or 3 disulfide bonds which make it a very rigid little molecule which is not broken down readily). Because the toxin is small, you can readily synthesize these by chemical means - by peptide synthesis as it is called - and so where you might only be able to extract a few micrograms of the natural toxin from the animal you can then determine its structure and then chemically synthesize gram amounts of it - and that is the route that is being taken by the pharmaceutical companies.

Tim Allen: So are you breeding up little snails in the lab, or.. ?

Bruce Livett: I wish we could breed them. It is very difficult to breed them because they develop as veligers and these tiny little veligers will float out and go around the tank and be lost in the filtration system - and also they requre a number of different types of plankton to develop and survive into adulthood and it is not easy to provide that environment in the laboratory setting. Instead, we go on a yearly Field Trip to an exotic place like Lizard Island or to one of the other Great Barrier Reef islands such as Lady Elliot Island or Heron Island, all of which have marine stations with marine aqarium facilities - and we collect the cone shells that we need and we bring them back alive to the laboratory where we keep them in marine aquariums in the Department of Zoology and the Department of Biochemistry and Molecular Biology at the University of Melbourne - and then we can milk them for their venom.

Tim Allen: ..and what is the research that you are currently working on within Australia ?
Bruce Livett: The research that we are currently doing is focused on what is known as the nicotinic receptor - that is the receptor that the nicotine in cigarettes hits ! - and there is currently great interest in nicotine addiction - and we are looking for a specific conotoxin that will inhibit the nicotinic receptor. There are conotoxins known that will inbibit the muscle-type nicotinic receptor, the type that you might have in a leg muscle at the end of the nerve, but there are relatively few specific nicotinic antagonists, as they are called, that hit the neuronal-type nicotinic receptor which is implicated in diseases as diverse as Alzheimer's disease and Parkinson's disease. These are the conotoxins that we are targeting, and we have found a few in Australian cone shells, and so - just last week we heard that we had a paper accepted into the JBC (The Journal of Biological Chemistry), which is one of the top journals in the scientific world in our area, and so we are now doing further work with that particular conotoxin.

Tim Allen: Bruce, should the average beachgoer be worried about the snails that they find in rock pools ?
Bruce Livett: They should be cautious ! Yes. I would advise them that they should not - if they see a cone shell which are easily identified by their cone shape ie. triangular shape - they should not pick them up and hold them out of their natural environment. When I have surveyed when people have been hit by cone shells it is always when they have taken the shell out of the natural environment and said (to themselves) "Oh here's a pretty shell. Look at that pattern, I must try to reveal it". So they start scratching away at the algae and the covering that is over the shell that makes it dull to reveal this beautiful pattern underneath - and the cone shell gets annoyed, naturally, and comes out and hits them. Two years ago we lost two Japanese tourists to cone shells on the Great Barrier Reef. One guy picked up the shell just on the beach near Cairns and he was found dead in his bed in the hotel in Cairns, clutching this cone shell in his hand. Another guy, unfortunately, put it down in the pocket in his bathers (Mmm) and .. nasty !

Tim Allen: (Yes .. Yes.. best not to talk about that one I think)
Bruce Livett: But I do think the tour operators do a very good job of warning people not to pick up anything from the Great Barrier Reef. They should look at it but leave it alone - and particularly taking cone shells out of their salt water environment can be very nasty.

Tim Allen: Now, if people want to learn more about "killer snails" and the cone snails in particular, there is a great Web site (..thank you, BGL).. and it is called "Charmaine's Killer Snail HomePage" - so there you go - "Charmaine's Killer Snail HomePage". If they just put those words in and search the Search Engine, it will come up fairly readily I would say - otherwise, Is there another .htm or URL they can search ?
Bruce Livett: Yes - fortunately we have the top rating site in this area so if they do that they will get there ok. I can give you the URL if you like ?

Tim Allen: Yeah, OK. Give the URL. If people out there have a pen handy.
Bruce Livett: Right, well here's the indigesible URL for you. It is "http://grimwade" (that is named after Russell Grimwade School of Biochemistry and Molecular Biology) - so it is "grimwade.biochem.unimelb.edu.au/" (and then a "tilde" ~, which is one of those wiggly little things on the keyboard, top left hand side) and then bgl (which are my initials) and then "/content.htm"

http://grimwade.biochem.unimelb.edu.au/~bgl/content.htm

NOTE: NEW SITE http://grimwade.biochem.unimelb.edu.au/cone/ <-- Click this one

Tim Allen: Thanks very much - Bruce Livett there from the Department of Biochemistry and Molecular Biology at the University of Melbourne. Bruce, thanks for coming into the studios this morning.
Bruce Livett: Pleasure Tim. Thanks for having me.

Tim Allen: You are listening to Radio Marinara. The time is - well, just past 20 minutes to 10 am. Stay tuned because Brett Illingsworth from Dive Under will be giving you the Dive Report for the long weekend. Let's hope it is better conditions under the water than what it is above. You are listening to Radio Marinara…[music lead in to next segment].


Do you have any positive comments or/and questions ? Please contact Dr. Bruce Livett, Dept. Biochemistry & Molecular Biology, University of Melbourne, Victoria 3010, Australia


Copyright 1998 Dynamix@WORK! All rights reserved. Last updated on July 28, 2004.