Author Archives: Alison

Tall ships and warships and kayaks, oh my!

Cross-posted from Kayak Yak Yak.

September 18, 2011

So, on paper (on screen), the itinerary looked awful, despite my having the tolerance for lousy connections that comes with being a hardened veteran of public transit. As of Labour Day weekend, only one of the four navettes to Parc des Îles de Boucherville is still ferrying. The (hourly from 1000) ferry leaves on the hour. The (hourly) Sunday bus to the ferry arrives at the nearest stop 2 minutes to the hour, with a long, high footbridge over the highway between stop and dock. On the way back, the (hourly until 1730) ferry leaves the island at half past the hour. The (hourly) bus leaves the stop near the dock about 28 minutes past the hour. Added to that, this ferry pulls in at a jetty on Île Charron an extra 1 km of path away from the kayak rental.

But it was an ideal kayaking day, and I live in the neighbourhood of a stadium. The morning of a big game usually features successive serenades by tow trucks, brass bands (though I harbour a secret pleasure at the irreverence of the Pink Panther at 9 am on the sabbath), and vocals (“Oh Ceh-neh-deh!”). There should be a fine for amplifying any singer who cannot. Hit. That. High. Note. On. Key. I had been out at Parc de la Riviere (I will find that grave accent on the keyboard yet) the previous Sunday and spent 7 hours in a kayak (probably qualifying as one of my 5 longest paddles), so I decided I would head for the ferry.

Leg one of the Great Trek was by Bixi down to the Old Port, which I found busy for a Sunday forenoon, having forgotten the tall ships had sailed into Montréal on Thursday. Four were still in dock, and I paused to take a photo and then carried on west along the promenade. The next nautical attraction was not one to pass with a mere snapshot: frigate HMCS Montréal moored with pennants flying and gangplank down. I found a dock for the Bixi and trotted aboard for a good peer at the ship and all its gear (at least the gear they were willing to show off). Since kayaking leaves one very aware of stability, I am still baffled as to how they launch their Sea-Sparrow missiles without, well, turning over. The angle of the harpoon anti-ship missiles made sense, in that when the rig is in launch position the thrust must be towards the middle of the ship, but the Sea-Sparrows are housed laterally and appear to launch vertically. Must read up.

Around 11:30 I collected my Bixi again (same bike), and set off for Parc Jean Drapeau, which involves describing a big hairpin to come at the Parc via Pont de la Concorde. I had to make Metro Longuiel-Université de Sherbrooke by 41 minutes past the hour to catch the 81 bus – the bus that would probably arrive in time for me to miss the ferry. I continued at my own pace, pausing to take a couple of pictures from the other side of the harbour, and rolled up to the Bixi station beside the Metro at Parc Jean Drapeau at 12:20. Lots of open docks, check. None of which were willing to accept my bike. Finally, after I had tried every dock at least once, one grudgingly gave me the green light, and freed me to plunge down the stairs into the metro station. . . . As the masses began pouring out, a outbound train having come and gone.

So there went another 5 minutes. I rode 1 stop under the river, got off the train and scampered. Well, proceeded on impulse power. Seemed silly to miss the bus now. The bus complex has big windows onto the bus parking area, so you can see your bus on approach, and know when to engage warp engines. I caught the bus, 12:41. Along with a little tot whose mother – who looked about thirteen years old – would never lose her in the long grass. Or, indeed, anywhere short of a rock concert.

The bus hit its mark at the appointed time, and I scurried for the footbridge. From the footbridge, I saw the ferry below at its dock, with a line of people with bikes, loading. Scurry faster. Down stairs, along a few dozen yards, skid down gravel path, and arrive to find that they were full and had to come back for myself and another couple. Which they promised to do. So we hung out on the docks, bobbing as the speedboats tore past, and 10 minutes later, back came the ferry. We’d loaded and cast off when a young family, complete with tot (silent tot) in trailer bike, pulled up, and our captain looped back to collect them. With that and a couple more strays, we had a full cargo of people and bikes.

It’s a quick trip, just across the narrow strip of the St Laurent between Îles de Boucherville and Boucherville. We offloaded adjacent to a boat ramp that was already stacked with boat trailers depositing boats. Once again, I was the only bikeless passenger, and was shortly all alone (but for a few assorted butterflies), tramping around the opening of the highway tunnel (I’m sorry, it is just so wrong to have a 4-lane highway come up from the underworld on an island which is a park). Across Île Charron on the way to the entrance of the park, and down the south side of Île Sainte-Marguerite. I estimated it would take me close to an hour, and it did, though I was not hurrying. Temperature was probably close to 20C, but the air was so clear that the sun had a Calgary feel to it, hot. There was a constant silver noise of cicadas.

I reached the location d’embarcations about 1:40, and paused for a quick lunch before getting to the point of the day. No queue, no crowd on the beach, quite a contrast to my first trip. Red Kayak, Ookpik, with a rudder I never did get to cooperate with me, fixed unfeathered paddle, which felt too short until I was in the reeds. I calculated I had about 2 hours before I would have to make tracks for the dock, because if I missed the 1730 ferry my options would be (a) hitch a lift, (b) call for a taxi, or (c) check into the hotel on the island until next Saturday. I had no desire to fight with criss-crossing wakes, even if there was no wind to speak of, so I turned left/north/up La Grande Riviere and, well, the pictures speak for themselves. Blue sky, round little decorative clouds, and water like glass. I threaded through the reeds for most of the way along the north leg in Chenal le Courant before I hit my turnaround time. There were a few close encounters with fellow paddlers and canoeists in the narrow channels. Canadian politeness seemed to make us compete as to who could move furthest out of the way, leaving 2 boats discretely trying to extricate themselves. Two herons, on the wing, and what I suspect was a kingfisher, with a striking white stripe on the neck. In the photos, the water looks faintly marbled from the weeds, visible through the clear water. An abundance of tiny fish in the shallow waters of Grande Riviere, and some larger ones in the deeper open areas of Chenal le Courant.

Back to the rental, park boat, deliver gear, collect ID, take a couple more photos, knowing I would probably not make another trip before the ferry stopped running after Thanksgiving weekend. Paths were busier on the way back, but still not nearly as busy as they were in July. Arrived at ferry dock about 5 pm, thinking I might be lucky, and they might be shuttling passengers at need, but there was no sign of the ferry. I sat and and watched the antics at the adjacent boat ramp, with boats ringed around the ramp and cars and trucks with trailers queued back along the road waiting to pick up or offload. I’d thought the ferry might be full, which was the other impetus for getting back early, but when we left, we had about eight aboard, including a flushed couple of cyclists who had done a very fast final km. By the time I reached the bus stop in the shadow of the bridge, I was looking at a 50 min wait.

I started walking, along Boulevard Marie-Victorin, with road and humming highway between me and the water, and standard suburbia on the other side. My knees had been wingeing ever since I got out of the kayak, and they stepped up their complaints as the road opened out before me, though it was the low sun in my eyes that eventually made me decide just to stake my spot in a shaded bus shelter, and wait. I detoured via a Macs for a bottle of gatorade and a chocolate bar. Call it rehydration and replenishing glycogen stores, ok? And settled down to read “Sheepfarmer’s Daughter” (Elizabeth Moon) from the Baen Free Library on my iPod touch until the bus came.

Bus to Metro Longuiel-Université de Sherbrooke, Yellow line to Berri-UQUAM, Orange to Metro Sherbrooke, and La Popessa spaghetti house for fettucini a l’Atlantique, which seemed appropriate. So in summary, I kayaked for 2 hours. Biked for probably 2 hours. Walked for 2.5 hours (not counting the time spent aboard HMCS Montréal). Rode various forms of public transit for another hour or so. Definitely did not fulfil Alison’s optimum of paddling time > travel time. But I was lucky on the way out, and psychologically prepared for the return, the sky was blue, there was no wind, and the water was like glass . . . [Edited September 22 to add some more photos]

Parc nationale des îles-de-Boucherville

Although Parc nationale des Îles-de-Boucherville has year-round auto-access (by tunnel and autoroute, no less), getting there by public transit is more challenging. Last year I missed the 3-or-so month season of the navettes (ferries) to and from the park. This year I was determined to make it over at least once. A couple of weeks ago, I’d looked at the temperature and wilted. This weekend, newly hardened by our “heat dome”, I didn’t look; I made my plans, packed my bag, and set out.

The navette from the Montreal side leaves from Parc Bellerive on the east island. With Sunday bus service, I figured I was going to miss the first ferry at 10 am, but it was still there when I trotted up to the dock about 5 minutes past. I paid my $8.00, clambered aboard. Brisk zip with a certain bounce along the St Laurence to the dock on Île Charron (that’s the incoming dotted line to the upper left of the island-mass on the map), past a formidable looking radar monitoring station and into a rectangular bay of calm stale water, with a slight whiff of anaerobic mud.

This did not put me into the Parc proper; rather disconcertingly, I climbed up the short path from the dock and I found myself plunk beside a roaring highway, rising up from underground. However, a dozen or so yards away, a cinder track turned off to the left and I left it all behind. All the other ferry passengers had bicycles, so I shortly found myself alone, tramping across Ile Charron; the map said 3.5 km to the Centre de Locations, about half way down the channel between Île Sainte-Marguerite and Île Saint-Jean. I’ll compress the land-bits, save that the temperature was already heading for the high-whatever and I was feeling the lack of shade because of the well-cleared zone around the path, I gave one of the local lifeforms a flying fright, catching only a glimpse of reddish flank and a great thrashing wave retreating through the tall grasses (I was put in mind of Sheri Tepper’s Grass, though obviously it was not a foxen). I crossed over a road-access, and walked by two parking lots, something that seemed mildly surprising and ever so slightly indecent. At the entrance I paused to puzzle over whether or not I needed to put a bit of my ticket in the self-pay envelope to establish I had paid the entrance fee – which I knew was included in the ferry fare – but decided I probably needed it with me. As it turned out, I was right.

Once in sight of the rental shack, I had a gazpacho-break in the broad picnic area, and then went and snagged myself a boat ($35 for 3 hours). I did not (remiss of me) take a note of the name, save that it had 6 letters, and was Inuit. The kayak was bright red, hard glossy plastic, with a rudder, probably a 14′. Very comfortable seat with good back support. Foot-pedals on a strap, sparing me the usual contortions adjusting them as I floated offshore, having cleared the busy beach. I need to bring my sandals next time – paddling barefoot is too hard on the heels, but walking 7 km in those sandals is too hard on the feet. On the deck, waving like a tongue, was a laminated Parc map about 9 inches long, secured at one end. The man at the booth assured me the circuit on the map was doable in 3 hours, and that I should start by heading south.

However, in not looking at the temperature, I also missed taking note of the wind. I have no photos of the initial paddle down Chenal Grande Riviere. The paddle I had was fixed, not feathered, and felt shorter than I was used to, and I needed to hold my course between the reeds and various pleasure-boats, against the wind. Later I read it was 15 kph N with gusts up to 30 kph, per environment Canada, but even by Montréal’s idiosyncratic definition of directions, that wasn’t a north wind. I hugged the reeds along the right shore until the debouchment into the Fleuve Saint-Laurent, checked for oncomings, and slogged across the choppy water to start along the south shore of Île de la Commune. There are no photos of this section, either, because I still had the headwind, and in addition, had wakes kicked up by the assorted pleasures boats’ more energetic cousins, all the way to the turn-in to Chenal la Passe. I also had company, a couple in a red rented double, a family of three in a canoe who could not all paddle in the direction at the same time, and a couple probably in their own boats, bold enough to swing out clear of the shallows and the worst of the chop. I think they all had more ambitious plans than I, because when I turned into the Chenal la Passe, none of them followed me.

Something else did. I was admiring the wooden bridge which carries the foot/bike path over the Chenal, when I heard a clatter of outboard behind me. It refused to be willed away, and further asserted itself with a puff of diesel flatulence, before parking in the middle of the channel. I can haz torpedoz, I darkly muttered, and scooted past before the fishhooks came out. I met the breeze again coming down, making that five points of the compass it covered, though it was much lessened. And when I got to the top of the Chenal and turned west, putting the wind more or less at my back, and hitched myself around (flexibility exercises! must do!) and discovered that although I had not checked that the rudder was unhooked, it was unhooked, and I could flip it down – suddenly my Sunday workout became a Sunday cruise. On both sides I had reeds and what seemed a thin line of low trees. Straight ahead, I could just see civilization in the form of a pylon. The omnipresent city hum was almost inaudible. On the way up the Chenal, I caught sight of a kingfisher, glimpse of blue and pale, dashing past, a little mustard-coloured finch-like bird, dotting from leaf to leaf, the ubiquitous red-winged blackbird, and the hovering black-winged seagulls. Though the map suggested one hugged the shore, I needed to steer wide around mats of frothy spew of yellow-green weed (the only way to describe it). In amongst the reeds, I could see water-lilies. There was the occasional white one, open, and faintly luminous, with the peppering of tiny insects in the base of the cup, but more of the closed fist-like yellow ones, pushing above the waters on their stems.

Then the reeds closed in. Shiny, green, about 3 feet high, with the wind hissing through in a mean-girls whispering; they narrowed the passage down to a single navigable channel. The movie clip captures the motion and something of the sound, though coarsely through the little microphone. I think that sudden flight of birds is of red-winged blackbirds, and the creaking is the sound of my plying the rudder, steering. Just after I had put the camera down, two double kayaks, as red as mine, appeared before me, and we were occupied in trying not to run into each other as we maneuvered past. I heard the occasional grunt and mutter of a heron, but only saw one, when it launched to my left and floated parallel to my course for several impossibly slow wingbeats, before it settled out of sight again. It was one of those long suspended moments that are still far too short to go for a camera. Something behind me started shrieking and crying in piteous alarm, though I have no idea whether I was the provocation, or what it was. Once out of the reeds, I paused to drink yoghurt turned liquid the warmth and finish my Jamaican pastry. Then I carried on down the channel past assorted route markers and the occasional cryptic sign, thinking about the unmistakable high summer blue-green of the foliage, just before it starts to look tired.

Chenal la Passe turned into Chenal Grande Riviere, and I was very shortly back among the pleasure-boats, with the bronzed and bodacious disporting themselves. A large shaggy golden retriever on the deck of one gave the peasant in her kayak the stern retainer’s eye. The circuit had taken me 2:15 hours, and though I was tempted to turn back amongst the reeds, I was tired and my eyes were dry and scratchy. So I beached, off-loaded, and, the attendants being occupied, discovered that using the trick of lifting the boat onto my thighs before shouldering it, I could heft a plastic kayak pushing 50 lb. Though I would not have wanted to load it onto a roof-rack solo, and maneuvering with only a 90 degree field of view and 7 feet of kayak sweeping fore and aft is not something I like to do with as many people around – so in future I will wait. But I returned it to its rack without injury to myself or anyone else, and my return was timely, because the line at the rental shed was getting ever longer and the supply of visible boats, dwindling.

Back on land, I’d the choice of walking back to Île Charron and taking the navette back to Bellerive, or continuing on to the other dock, walking along the shore I’d just paddled beside, crossing over Chenal la Passe and getting a shuttle over to Boucherville itself. The distance, walking, was about the same, and I wanted to scout out the second route, which seemed to me the most feasible way of bringing the Dragonfly over. So I got to see a quite different aspect of the island, because although from the water it looked wildish, inland, it had been cleared and put to the plough and looked not unlike parts of central Saanich. I crossed the Chenal Grande Riviere on the cable-ferry, and the Chenal la Passe on the bridge I had admired. On foot, ducking down the grassed footpath which ran parallel to the track, I was in a minority, most everyone else being on bicycles. This time I knew I’d miss the ferry, which according to the schedule left on the half hour, but I was pleasantly surprised to discover that, whatever the schedule said, the ferry was only pausing to off- and on-load passengers. My ticket turned out to be a return, and I hopped aboard, bound for Boucherville. The young man at the helm took off with brio, including some wide swishing turns that kicked up white spray and were – fun. Yes, indeed, maybe I can understand the appeal of going really fast over the water. (But I didn’t squeal.) My luck held at the other side, because after a short, pleasant wait, the hourly bus (81) hove into view, and I had even had the foresight not to spend all my change. The one downside of the southern route is the Boucherville bus is a separate fare from the Montreal one; on the other hand the ferry is cheaper. And so to the Metro station and back into town.

Here’s the first selection of photos; there may be more.

Lessons learned along the way

In an exchange on a listserver I am on, the question of writing lessons learned along the way came up. This was my list . . .

Published novels are the finished product: one never sees the messes, failures and train-wrecks on the way, so one is completely misled as to how easy certain things are to execute. The downside of a diet of the best is that the emerging writer can become inadvertently overambitious and try things that are too difficult for them.
I did two dumb things and two smart thing in my first novel. Dumb things (ie, things I wasn’t developed enough to do): writing a quest novel, and using that past-present structure that Ursula Le Guin made work so beautifully in Dispossessed. I didn’t realize until a year or so after Legacies came out where I’d got it from, and why I was so wedded to it. The sort-of-quest structure is difficult to pull off because it doesn’t innately have a strong narrative drive behind it. Smart things I did: having a single viewpoint, and having a character I had deliberately written as attentive and extremely perceptive. Sometimes, wrestling with the need to convey something essential via a viewpoint character for whom it’s not in character to notice that, I miss Lian.
Certain plots are more bomb-proof than others – they carry their own structure and drive with them. [cref Blueheart]’s initial plot is a mystery, and once I’d got that – the dead body in the ocean – it found its shape quite quickly, carried along by the central question of who and how. By midway through the book the reader actually knew everything, and it turned into a political novel, but by then the central conflict was established and on its way to the climax. I did myself an inadvertent favour, there.
Quest plots – frequently the first plot an SF&F writer tries – are not as easy as they look: certain choices have to be made to ensure the quest plot gets and keeps its narrative drive and doesn’t become picaresque (a right-on editorial comment about an early draft of Legacies). If I were writing a quest, even now, I’d make sure that what was being sought and who was seeking it were established in the first chapter, and not lose sight of that for a moment. I’m still not sure enough in my plotting to do the young man/woman goes off all unknowing and find his/her destiny on the way. I was unwittingly smart enough to have the quest front and center in the beginning of Legacies’ frontstory, interspersing it with the interleaved backstory in which Lian had to find his mission.
Passive, reflective characters fall under the heading of Advanced Work. Again, writers have pulled off the reluctant hero wonderfully, but life is much easier if a character wants something and goes after it. Lian climbing over the wall, throwing himself into the path of Lara and Rathla and the story itself, was a wonderfully liberating moment for me.
Sometimes the writer just has to give up and do what’s obvious – usually because they’ve set themselves up that way. In one of my unpublished novels I was resisting a particular idea because it seemed too obvious. When I finally accepted that it had to be that way, a whole lot of other problems were suddenly solved, because my characters’ repugnance (they didn’t like the idea any more than I did) prompted them to actions that led directly to the showdown. Moral: It’s a bad idea for the writer to argue with their own story.
Even after (almost) 9.5 novels, I still don’t get control of the plot until my second draft (or later). I’ve just had to do a massive overhaul to keep two of my main characters on the scene for a major action setpiece (this was [cref Shadowborn]). I also had difficulties setting up a crucial event in that conflict, because I needed not to surprise the reader, but I knew that if one of the characters knew about it, it would be out of character for him to leave. So overhaul. And it works. So. Much. Better. Moral of the story: keep the viewpoints where the action is. As long as the action is essential to the plot.
If I reach the end of my first draft, and it isn’t right (usual metaphor: large plate of spaghetti, stands slithering over the sides), I start cutting. I usually have a fixed idea of the endpoint from fairly early on in the novel, and I reshape the novel to line up with the end. I cut out everything that that isn’t related to the end. Then I put in everything that’s missing.
On the other hand, all the scenes that end up on the cutting-room floor mean that by the time I get the scene I need, it practically writes itself because all the decisions are made and I have the characters rounded out. Ibsen described his growing familiarity with his characters through successive drafts. In the first draft he knew them as if he had met them on a train (‘One has chattered about this and that’). By the second draft he might have spent a month at a spa with them (‘I have discovered the fundamentals’). By the third draft, he knew them thoroughly (‘as I see them now, I shall always see them’).
I try to obey Chekov’s Law (‘One must not put a loaded rifle on the stage if no one is thinking of firing it.’), which usually means I have to round up a certain amount of unused artillery during revisions. One of the downsides of writing a trilogy is that once [cref Darkborn] was committed to press, I was committed to firing off the guns lying around. Twelve of them, when I did the inventory in my notebook. I was delighted when I found a way to get four to pop off at once in the archduke’s breakfast.

Drugs from the Sea: 1. Cone snails and ziconotide

Cross-posted from Kayak Yak . . . Drug discovery from marine sources is an active area of research, and several drugs of marine origin have already reached regular clinical use. (There’s a whole journal dedicated to Marine Drugs. Open access, too). For quite some time, I’ve had the notion of doing a series of posts about these drugs, where they come from and what they do, and I’ve been tinkering with this first entry for about as long, trying to balance length with bio-geekery. So here goes.

In 2004, the pain-killing drug ziconotide (Prialt) was approved for marketing by the US FDA, some twenty years after Balmedro Olivera and Lourdes Cruz set out to find out how the sting from a 10 cm poisonous marine snail, Conus geographus, could kill a human many times its weight. C geographus (picture from Wikimedia commons) is a member of the cone snail family, so named for their distinctively shaped, colourful shells. C. geographus takes its name from its map-like shell pattern (photo from Wikimedia commons). It lives below the low tide mark in pockets of sand near the edges of coral reefs and atolls; on a map its distribution tracks a wide ribbon from Madagascar around the edges of the Indian Ocean, down through Indonesia, around the North coast of Australia and up the islands and atolls of the Pacific. To the biologist, it and its fellows are known as Class Gastropoda, Order Neogastropoda, Superfamily Toxoglossa, Family Conidae, while naturalists over the centuries have named the Apothecary Cone, Astrologers Cone, Hebrew Cone and Emaciated Cone. The dinosaurs were already extinct when the first cone shell was pressed into the fossil record, some 55 million years ago, but they now form a family around 700 species strong, which inhabits warm and tepid shallows around the globe. The more common species can be had for a pleasure-dive in reef waters, or a stroll along the ocean, while particularly rare and handsome specimens have been auctioned for more than the price of a painting (in 1798) or a family saloon car (1960). Occasionally, their price has been a life: 30 or so people are known to have died of cone snail stings, mainly from Conus geographus.

Cone snails’ dietary aspirations might seem, on first blush, overambitious: they are carnivorous, with a taste for worms, other molluscs … and fish. However, per Ecclestiates, the race is not to the swift . . . Cone snails generally use one of two hunting strategies, harpoon or net, and their secret weapon is poison, a cocktail of venoms tailored to hunting style and prey. The cocktails contains 50-200 individual toxins, and vary between species, so that there are an estimated 25 000 plus toxins across all the known cone snail species. The venom of the harpoon-wielding snail Conus purpurascens contains a mixture of fast-acting toxins that produce a nerve paralysis, and slower acting toxins that produce muscular paralysis. When a fish comes within range, the snail jabs at it with a venom-filled tooth held on the end of a proboscis. A stung fish can be paralyzed within two seconds, its body rigid and its fins standing out as though shocked. One toxin jams open the sodium channel involved in the propagation of the nerve impulse [footnote i], a channel that ordinarily would close immediately to allow the membrane to reset itself. Another jams closed those potassium channels which normally would open to quench the depolarization. The membrane depolarizes, rapidly and completely, and nerve conduction stops. Even as this happens, a second, slower-acting set of toxins, acting on calcium channels, starts to paralyze the fish’s muscles. They block sites to which signalling neurotransmitters bind, and sodium channels which would open in muscle contraction. Net-wielding snails, like Conus geographicus favour muscle paralytic toxins; since they first engulf their prey and then sting it, they can afford the slightly slower onset poison.

Contoxins are very small proteins, 10-35 amino acids long, and at their length would normally be a tumbling mixture of floppy conformations in solution rather than a fixed protein fold—Proteins depend on their ability to hold conformation to function. Conotoxins, however, take advantage of a property of the amino acid cysteine. Under the proper conditions, two cysteines in a peptide chain will link to each other, bringing their respective pieces of peptide chain into alignment. Conopeptides, small as they are, each have two or three pairs of cysteines, which cross-link to create a tight little package (3d structure of Ziconotide as the August 2006 molecule of the month at 3dchem). Since they are tightly folded, conotoxins waste neither time nor energy shifting into the right shape to bind to their target. There are two measures of quality of any interaction between molecules: how well a molecule discriminates between its own and all other binding sites, and how strongly it binds. By those measures, conotoxins are finely tuned, with certain conotoxins able to select between nerve cell sodium channels and muscle cell sodium channels, and others able to pick and chose between subtypes of calcium channel. Contoxins are several times more selective than peptides from snake and scorpion venoms. A measure of the strength of binding is the dissociation constant, a ratio of the amount of unbound toxins to the amount of bound toxin at a giving concentration; for the conotoxins those are of the order of 10(-9) or 0.000000001, or for every unbound toxin molecule, there are one trillion bound.

Drugs are often limited in their usefulness by side effects, some of which result from binding to molecular sites other than the target sites. For that reason, the conotoxin peptides, all 25 000-odd, with their strong, specific binding, are of great interest to scientists and several companies have investigated cone shell toxins as a source of drug candidates. Ziconotide (aka Prialt, from Elan Pharmaceuticals) is the first conotoxin-derived drug to pass successfully through all the stages of clinical drug development. It is a synthetic omega (calcium-channel binding) conotoxin from Conus magus, the Magician cone, which binds specifically to (calcium) channels in nerves in the spine which carry pain, and has proved effective in relieving pain for patients with intractable severe pain who either do not respond to or cannot tolerate other drugs. It’s not an opioid, therefore doesn’t produce tolerance, and can be combined with other drugs. But it’s still far from ideal: it has to be administered by intrathecal injection (directly into the fluid around the spine), which means it has to be given by an anaesthetist or by an implanted pump. The dose has to be increased slowly to decrease the risk of side effects, the onset of effect slow, response to dose changes is laggardly, and it can produce severe neurological and psychiatric side effects (Williams, 2008 PubMed abstract; Schmidtko, 2010 PubMed abstract).

To date, no other conotoxin-derived drugs have made it through clinical testing and into clinical use. Olivera in 2006 listed five in Phase I (first human) testing, mainly for pain, and their status in 2011 gives a snapshot of the vicissitudes of early phase drug development and the precarious life of small biotechnology companies: three of the companies involved appear to have either gone under or moved away from conotoxin development, and I am hard put to find evidence of progress on four of the compounds. The fifth (Xen-2174), which inhibits the uptake of the neurotransmitter norepinephrine, is in Phase II trials. Nevertheless, investigation continues; there are at least 24996 more conotoxins to go . . . A conotoxin derivative that can be taken orally has been developed. Conotoxins are being studied for their potential to protect brain tissue in stroke and heart muscle in heart attack, where part of the damage is known to be caused by uncontrolled leaks of ions across membranes [Twede et al, 2009 Full text]. And work with conopeptides has also identified other pathways involved in severe pain, leading to the development of non-conopeptide drugs directed at these pathways.

Footnotes and references.

[i] An aside on nerve conduction. It is orchestrated by the opening and closing of protein pores in the cell membrane of the neuron, which pass, according to their filter characteristics, sodium, potassium, or calcium ions. The sequence proceeds as follows: a trigger signal arrives, whether an electrical signal from another neuron, or a chemical signal. The membrane is held at a resting potential, a static voltage, with an excess of sodium outside the cell and potassium inside. When the impulse is triggered, sodium channels open, and sodium flows into the cell. The membrane depolarizes, losing its charge. Once the depolarization proceeds to a certain point, the sodium channels close, and potassium channels open, quenching the depolarization and allowing the membrane to reset to receive the next impulse. As each patch of nerve membrane is depolarized, it triggers depolarization of the next downstream; thus the impulse travels.

Olivera BM. E.E. Just Lecture, 1996. Conus venom peptides, receptor and ion channel targets, and drug design: 50 million years of neuropharmacology. Mol. Biol. Cell. 1997 Nov;8(11):2101-2109.
Olivera BM. Conus peptides: biodiversity-based discovery and exogenomics. J. Biol. Chem. 2006 Oct 20;281(42):31173-31177.
Terlau H, Olivera BM. Conus venoms: a rich source of novel ion channel-targeted peptides. Physiol. Rev. 2004 Jan;84(1):41-68.
Wikipedia on Conus species, Ziconotide, ion channel.
ConoServer (peptide sequence and reference database).

Shading between curves in R

As a R learner programmer, it took me unconscionably long to work out how to use polygon to shade under and between curves, despite searches of the R manual and R-help – they just didn’t start far enough back. So, for anyone else scratching his or her head over polygon (and so I can find it again when I forget how it’s done), here are the series of steps I went through to figure it out.

The function takes in an x vector and a y vector, defining a set of coordinates that, in order, taken in order trace around the area to be shaded. Thus for a set of points 1-10, defined individually as x.1, y.1 to x.10, y.10,

x <- c(x.1,x.2,x.3,x.4,x.5,x.6,x.7,x.8,x.9,x.10) y <- c(y.1,y.2,y.3,y.4,y.5,y.6,y.7,y.8,x.9,y.10)

The area inside these points is shaded by

polygon(x,y,col=gray(0.8))

To apply this to two curves, both normal distributions between -3 and 3, one half the height of the other

x <- seq(-3,3,0.01) y1 <- dnorm(x,0,1) y2 <- 0.5*dnorm(x,0,1) plot(x,y1,type="l",bty="L",xlab="X",ylab="dnorm(X)") points(x,y2,type="l",col="red") polygon(c(x,rev(x)),c(y2,rev(y1)),col="skyblue")

The first half of the x-vector in the polygon is just the values of x itself, corresponding to the part of the polygon that is tracing out the upper curve along increasing values of x. The second part for of the x-vector in the polygon is the reverse of x, corresponding to the part of the polygon that is tracing out the lower curve along decreasing values of x. The first part of the y-vector is the y values of the upper curve, and the second part of the y-vector is the y values of the lower part of the curve.

That shaded the area between the curves along the full plotted range.

To shade only a defined portion, say the area from x=-2 to x=1.

x <- seq(-3,3,0.01) y1 <- dnorm(x,0,1) y2 <- 0.5*dnorm(x,0,1) x.shade <- seq(-2,1,0.01) polygon(c(x.shade,rev(x.shade)),c(dnorm(x.shade,0,1),0.5*dnorm(rev(x.shade),0,1)),col="yellow")

To shade the same defined portion as a gradient, from red to yellow (from the built-in heat.colors palette):

x <- seq(-3,3,0.01) y1 <- dnorm(x,0,1) y2 <- 0.5*dnorm(x,0,1) x.shade <- seq(-2,1,0.01) par(oma=c(1,1,1,1),cex=0.7) plot(x,y1,type="l",bty="L",xlab="X",ylab="dnorm(X)") points(x,y2,type="l",col="gray") l <- length(x.shade) color <- heat.colors(l) for (i in 1:l) { polygon(c(x.shade[i],rev(x.shade[i])),c(dnorm(x.shade[i],0,1), 0.5*dnorm(rev(x.shade[i]),0,1)),border=color[i],col=NA) }

This draws a succession of individual polygons between the curves, adjusting the color along the gradient as it goes. (Note that the loop above is for i in one to letter-L).

Alison Sinclair

science, medicine, science fiction, and fantasy