Thursday, April 30, 2009
There She Be
The place was Floodwood Mountain Scout Reservation in New York state; or, to be more specific, that summer camp’s West Pine Pond. Three of us patrol leaders, our members off doing whatever they did when we weren’t tormenting them, got bored of an afternoon and decided to take a sailboat onto the lake. We checked out a Sunfish, piled on, and tacked out onto the water.
Well, three young teenagers are too many for a little Sunny. We were having trouble merely hanging on and staying afloat, let alone maneuvering a craft with which we were only a couple of lessons away from pure novicehood. Perhaps it was inevitabile, given nobody else on the pond was much better at it; perhaps a little miscreance on the part of the other kids played a role — but the next thing we knew we were being rammed, broadside.
The bow of the other Sunny skipped atop our deck, slamming into Skip Remington — I swear to God, that was his name. Skip was skinny as a rail, looked like he would blow away in a stiff wind; but he was also a berserker. Hurt and angry, giving an animalistic bellow, he grabbed their bow with both hands and, impossibly given the wind resistance of a sail and the water resistance of a keel, flipped them over. We sailed away, hooting at them as they scrambled to de-capsize.
We took the moment to take stock, and realized that the encounter was not only not traumatic — it had actually been kind of fun.
“Let’s sink another one,” I said.
So we picked out another sailboat — this one, shame on us, crewed by a single, small boy — and bore down on it. I don’t know how I wound up the unofficial skipper, but at this point I said, “Pull up on his windward side — that way, we’ll becalm him.”
For yes, little geek that I was, I’d read up on windjammer battle tactics, and new the secret of the weather gauge — the fact that, when one sailing vessel puts another downwind of it, the upwind craft literally steals the wind from the other’s sails. The hapless downwind vessel is rendered therefore unable to maneuver, and vulnerable to the upwind craft’s cannon.
Well, we didn’t have any cannon, and I’m not sure what my plan was supposed to be at that point — because events overtook the pace even of my fevered little brain. Inexperts that we were, we’d jibed — turned our stern to the wind, which in a fore-and-aft rigged boat like our little Sunny, meant that our sail suddenly caught the breeze and swung around violently. We had the luck of the unrighteous, though, since given the 50-50 chance of either pitching us off our deck or slamming into the other boat’s mast, it did the latter.
The force of the hit neatly flipped him over. A second Ship Taken, Sunk, or Burned: we were pretty obviously the undisputed scourge of West Pine Pond.
Sailing away, we felt much of ourselves — so much that our next choice of encounter was with a rowboat, which resulted in a lot of splashing and invective but nothing by the way of a conclusive result. At that point a camp counselor on a motorboat — the U.S. Navy of Floodwood Mountain, in effect — came out to arrest us and banish us from the waters for the rest of the day.
I bring this story up because our entry this week has to do with the crucial question asked by all pirates — as well as all dog handlers: Where be she?
I’ve burned the Webwaves on at least one dog-handler list regarding my conceptual difficulty understanding how in the world a dog can tell the direction of a trail of scent on the ground. I know they can do it; I just know enough about the difficulty of the task to wonder how.
An airscent dog, picking up the smell of a search subject on the wind, encounters not a uniform cloud of scent but a discontinuous, complex cloud of intense filaments of scent, with little or nothing to smell in between. The task of figuring out the direction it’s coming from would be a killer, if it weren’t for the obvious clue: the wind direction. Now, wind directions change, and so the filamentous cloud isn’t always a straight shot upwind. But that’s a refinement of a strategy that basically depends on there being at least a little air movement.
Trailing dogs have no such easy directional clue. Because the scent in the air is discontinuous, I think it’s probably safe to say that a ground trail is essentially a “footprint” of discontinuous filaments on the earth and vegetation. But regardless, you’ve got a trail, possibly hours or even days old, in which a dog, to tell which direction she has to move, presumably has to detect an increase of intensity between pieces of scent that fell from the subject’s body seconds apart.
Now, there’s always the possibility that a dog’s nose is sensitive enough to discern the one-gazillionth difference in intensity between the two bits of smell. But I’m leery of any argument that ends with, “because dogs’ noses are so awesomely sensitive.” I want to know how, and when it seems impossible to get from point A to point B — even when I can see it happen — I get the feeling that we’re missing something important.
Well, Akihiko Nishikimi and the Crazy 88 of Kyushu University and elsewhere have helped make my life even more complicated; they figured out the internal mechanism by which neutrophils — white blood cells that ooze their way toward infections by following a trail of chemical signals called chemoattractants — create a pseudopod that allows them to crawl in the direction of the infection. What caught my eye, though, was a comment in an accompanying commentary that mentions that the needed chemical structure “accumulates at the site of the plasma membrane that senses the highest concentration of the extracellular stimulant.”
Now hold on a second: a neutrophil is only 12 to 15 micrometers across — about 1,700 of them lined up side by side would make an inch . Assuming a concentration swing like that of the chemoattractant interleukin-6, which can vary by 1,000-fold in the bloodstream, that means that in order to find its way from, say, the entrance of my femoral vein to an infection in my toe — about a meter distance — that white blood cell would have to detect an average concentration difference, if my math is right, of 2 percent or less from one end of the cell to the other. Offhand it may not be hard to imagine a cell telling the difference between 102 and 100 from one end to the other — but remember, while it’s doing that it’s also sensing a level between 102 and 100 on all sides. And it doesn’t produce 102 pseudopods on the “hot” side for every 100 on the “cold” side. It just makes a pseudopod in the direction it wants to move: somehow, it's translating 102 vs. 100 into 1 vs. 0.
If you assume the gradient is uneven — say, the cell gets hit with a sudden increase when the blood flow brings a wave of attractant to it — it could make the difference across the cell much larger. But that would only explain how it starts moving, not how it keeps moving once that big increase is over and it has even less of a difference to detect. 
Except — and I’m guessing here — maybe the neutrophil isn’t a trailer, but an airscenter. Maybe the direction of the blood flow is the cue it needs to make sense of the complex series of attractant pulses that come its way, as the chemoattractant mixes turbulently in the blood and forms filaments of scent. Alternatively, the cells just ride the bloodstream, excited by the surge of attractant, until they’re right on top of the infection, and then the local concentration gets really high — but the impression I got was that the concentrations in the blood were enough to get them moving, which argues against that.
Well, either I’ve gotten something figured wrong or there’s more to the story. I’m going to see if I can learn more. If I figure it out — or find out if anybody else figured it out — I’ll give you all a hail.
 Which is actually pretty big, considering we’re talking about single cells here.
 Of course this is another unrealistic end of the spectrum. Probably the concentration falls off rather sharply from the source, then begins to level out to a low level farther out. This gives us the opposite problem: easy to find source from close in, even harder from far away.
Monday, April 20, 2009
Press the Buzzer ... 183 Times???
Sunday, April 19, 2009
Smoke and Mirrors
I waved encouragingly with my crutch, which is about all I can do to help at this moment.
A few months back, though, I was considerably more active. Maybe the most interesting training I did was my first, rookie go with the SCBA, a scenario in which my little team was to find a fake fire in a house filled with smoke from a smoke generator. Since it was a training, I had the rare privilege of being the nozzle man: the guy holding the business end of the hose and therefore the tip of the spear. Dan, a more experienced firefighter, played team leader, right behind me, two more teammates carrying various tools of destruction behind him.
The number one rule in entering a house on fire is that you never lose contact with the wall or your teammates. In a smoke-filled room, you simply can’t keep your bearings effectively and need that contact to know where you are, what your primary route of retreat would be, and whether anybody has gotten separated. If you have to leave the wall — say, to search for a patient trapped by the fire — you have a teammate who is in touch with the wall hold onto your ankle.
Everything, I should add, happens on your hands and knees (because the smoke and toxic gas tends to rise), tapping the floor in front of you for structural integrity.
Anyhow, and perhaps predictably, the very first thing I did was forget rule number one. Pumped up on adrenaline — even though it was only a training — I shot straight into the room, and immediately lost track of where anything was. Dan later told me, “I keep forgetting how green you guys are, or I would have reminded you.”
So here I am, facing the double uh-oh of realizing that I’ve butt-lost myself, and lost my teammates in the bargain . Three dead guys led by one dead idiot. Fresh fish, as they say …
Clausewitz wrote about the “fog of war:” the fact that, in the presence of an enemy whose numbers and disposition aren’t immediately clear, the unknowns multiply in your head, creating confusion so profound that trained officers in immediate danger for their lives can nevertheless freeze up and wait to be slaughtered. The ability to think under that kind of pressure can be trained to a certain point — people can learn to act reflexively when they’re scared to death, or for that matter excited or angry or whatever beyond the ability to think clearly. But to lead under those conditions is another thing entirely.
My metaphorical fog caused by the literal smoke at that training came to mind when I came across today’s entry — one of those wonky pieces that I just love. Jennifer C. Brookes and posse from University and Imperial Colleges, London, asked a simple question to try to dispel the fog of another question: why do odorants that are enantiomers — molecules that consist of the same components but which are non-identical mirror images of each other — sometimes smell the same and sometimes smell different?
First, a bit of background. Below are two versions of an enantiomeric molecule, showing how, though they are mirror images of each other, no amount of turning them around will get them to match up with each other. Generally, in biological systems, enantiomers have very different activity because a receptor that evolved to recognize one version can’t recognize another.
Public-domain image from Wikimedia Project, creator Yakobbokay.
Now imagine that your left hand is a receptor meant to interact with the version on the left. The black triangle attaching the hydrogen atom (H) to the carbon (C) at the center means that the H is sticking out of your screen; the dashed triangle attaching the methyl group (H3C) means the latter is sticking backward, away from you. So when your hand reaches out for this molecule from the left, your index finger touches the H, your pinkie the H3C, and your thumb the ethyl group (H3CH2C).
Now, it doesn’t take a lot of groping your screen to realize that you can’t get your left hand to touch the chemical groups of the right hand version of this molecule in this way — not without twisting your fingers around painfully. Well, mostly this is how receptors and their ligands work; though it’s a bit of a simplification, you can think of proteins and the molecules they interact with as Tinkertoy models, with atoms (the wooden disks with holes in them) attached to each other by chemical bonds (the dowels). The disks can twist around the dowels, but with enough attachments you’re fairly limited as to how everything can move.
The problem is, both versions of some enantiomeric odorants smell the same — which implies that, somehow, the olfactory receptors are achieving this kind of contortion. Which a single protein receptor isn’t supposed to be able to do . This problem with the receptor model for smell is one reason the vibration theory, a 1934 alternative to the more widely accepted lock-and-key model, refuses to die .
Problem is, some enantiomeric-odorant pairs, such as (1R,4S)-(+)- and (1S,4R)-(–)-fenchone, have the same smell (camphor, in fenchone’s case); but others, such as (4R)-(–)- and (4S)-(+)-carvone, smell quite different (former, spearmint; latter, caraway). Brookes and buds decided to take a survey of the structures of a large number of odor-characterized enantiomers and, with computer modeling, asked whether the flexibility of those molecules could predict anything about how similar each pair smells.
Most of the enantiomeric pairs, they quickly realized, actually are somewhere in between the two extremes: either they smell similar but distinct, or they smell the same but one is much more intense than the other. The phenomena of two enantiomers smelling pretty much exactly the same — or clearly different — were actually fairly rare.
But maybe their most interesting finding was, maybe, the opposite of what you might expect: the more flexible enantiomers were actually more likely to smell different. Twisting and turning makes two enantiomeric forms of an odorant less, not more, interchangeable.
That took me a moment to digest, but it actually makes sense. As I said above, to get an enantiomer to fit with a single receptor’s structure actually takes so much contortion that the molecules can’t do it. Ain’t enough flexibility in all of Christendom to make that work.
More to the point, the researchers propose an “other” way of looking at the odorant-receptor interaction that blends ideas from both the lock-and-key and vibration hypotheses. I’ll see that idea and raise it a gross simplification that may make some protein biochemists  wince:
Olfactory receptors, it turns out, are nearsighted.
Think of an odorant molecule not as an in-focus tinker toy, but a blurred (or fogged) version thereof. If you have an enantiomeric odorant, then, it looks to the receptor something like this:
Where the red and blue blobs are recognizable chemical groups, and the center of the mirror image is the asterisk.
Now, if you consider that odorant’s enantiomer:
This could, of course, be a vibrational thing. But I prefer the authors’ (not completely contradictory) suggestion that the receptor isn’t interacting with every form of an odorant, but rather with a rare contortion. It would explain why olfactory receptors are such sucky receptors — with binding affinities a thousand times weaker than “real” receptors, such as my old nemesis the insulin receptor protein. The damned things are only seeing the small fraction of the odorant population that’s twisted in exactly the right way, and so you need more of the odorant around just to have enough in the right deformation to fit the lock.
Still, I have to admit that ideas from the lock-and-key and the vibrational hypotheses may be coming together to answer the question more satisfactorily than either could do by itself.
The fog may be parting.
My own, personal, fog of battle parted when I decided to strike out, as straight as I could, in the hope of finding the far wall. I hit, by chance, an entryway to the next room. In it stood one of our instructors, who told me to assume I’d hit a solid wall and keep working my way around.
This time I had the sense to hug the wall, working around clockwise until I came upon a lit flashlight. The light, indeed, went off: I’d found our “fire.”
“I assume you don’t want me to blast the flashlight,” I said to the instructor, who’d followed me. The hose I carried was under full pressure: you can’t simulate what it’s like to carry a hose around on your hands and knees if it isn’t charged, it’s far heavier and more rigid than when it’s dead .
“No,” he answered, “don’t.” Instead, he had me blast the hose out a nearby window, thus demonstrating to us how you can use a water stream through a window to blow the smoke out of a room . Slowly, the smoke cleared, and the room came into sharper view: I could see the walls, and the doorway behind us.
The fog of battle, the envelope of ignorance, had dispelled. Which is what it’s all about, after all.
 Heather taught, I did precious little other than keep a teammate’s pickup truck’s tailgate warm.
 Which is still lit up, but full of Disney shit these days — like going to a God-damned suburban mall. I’m not sure they weren’t better off with the hookers and peep shows.
 Of course, we could always follow our hose back out — but I’d screwed the pooch on searching the room effectively for our fire.
 One possiblity is that there are two receptors, one for each version; but for a number of reasons the authors discuss, this isn’t a very attractive explanation.
 I am a true apostate of that school.
 All right, stop the snickering.
 An application, I believe, of the Bernoulli principle.
Friday, April 10, 2009
Some Assembly Required
Monday morning, we roll up to the same-day surgery center and undergo the million bureaucratic steps that I know help the staff keep track of who’s who and ensure safety — but are no less irritating for the knowledge. Finally, in my pre/postop suite, the IV line started in my hand and the anesthesiologist en route to deliver the sleepy time, my doc’s resident — a young, tall woman who could have been a fashion model , came to discuss the operation they were going to do on my right foot.
“Right foot?” I asked. “I thought we were going to do both.”
She looked dubious. “I don’t think Dr. ——— ever does both at the same time. But you can discuss it with her when she gets here.”
We did discuss it, and although my doc gave a number of good reasons for doing them one at a time, the most obvious to me now, two days later, is that I wouldn’t be able to move myself around at all if we’d done them both. Nevertheless, it was an unwelcome miscommunication to discover at that point, particularly since it meant the six to eight weeks I’ll be spending at limited activity will only be half the time I lose to the damned thing.
I was more than a little crestfallen; since we operated on the worst foot first, I’m seriously considering seeing how I get around with only one repaired, and maybe putting off getting the second one done indefinitely. We’ll see.
Anyhow, the moment we discovered the misunderstanding — or so it seemed — my doc started talking to Heather instead of me. That may well have been because they’d given me the sedative and I wasn’t going to be with them for much longer, but I confess that it felt like she’d decided which of the two was smarter.
Thanks to the magic of anesthesia, that’s all I remember, until waking up to see Heather there, my foot swathed in a nearly spherical bandage, ouchie ouchie. Better Half drove me home, where I’ve been slowly regaining something approaching normality, given the fact that I’m going to be off work this week and on crutches for at least a week longer.
Yes, pay no attention to the blog of last Sunday behind the curtain, my three days of crutches have lengthened to two weeks — another miscommunication, discovered yesterday when the doc’s office called to follow up and see how I was doing.
Now, I have a postop release form in my living room right now that says, “partial weight bearing, heel only.” But the first time I tried that, my foot told me, “Oh, no you will not,” and I figured I’d take it seriously. So when the assistant told me, “No, you don’t want to put weight on it, just keep it elevated and talk with Dr. ——— on Friday,” I was relieved to find out I hadn’t been babying it, just being appropriately prudent. Today I had my post-op appointment, and the picture was a little rosier than that: Monday I'll get the stitches out, and at that point I'll be off the crutches as well.
Still, I could take an attitude. I could dwell on 18 years of physicians insisting to me that the gobbledygook they’d put on paper was perfectly comprehensible to their lay-level patients, and I didn’t dare edit it. Let alone tell the story from earlier life when, as a biochemistry grad student, I was looking up drug names for my grandmother so she’d understand what the hell her doc had prescribed for her.
The fact of the matter is, I don’t really have that out. I speak gobbledygook pretty fluently. So I think, rather, that it’s more likely an issue of “presumed comprehension,” in which doc tells patient 90 percent of the message, and they both fill in the remaining 10 percent — only differently. Yeah, part of the doc’s job, just like mine, is to make sure the patient/reader understands. But I’m in no position to cast asparagus on that point. At least everything is going well in the recovery, so I’m not inclined to complain.
One thing I have learned in 18 years is that you can’t word anything so that everybody understands it; attempts to reach universal comprehension wind up with worse gobbledygook than if you just try to make it clear and direct in the first place.
Getting a clear message across is the gist of another entry from Donald E. Frederick & Co. from Leslie Kay’s group at Wire Mommy , in Behavioral Neuroscience this month. This is another installment in the ongoing quest to decipher the code by which odor-carrying molecules are translated into perceptions of smell in the brain.
DACSIH? has touched on this issue before; but this time I think it’s appropriate to take a step back and discuss more fully the standard hypothesis that the new work is overturning.
One good summary of the hypothesis can be found in a review paper about insect odor processing by Hong Lei and Neil Vickers, in volume 34 of Journal of Chemical Ecology (that issue, by the way, being a trove of information about how critters perceive and then home in on the scents that are important to them).
We first need to remember that, unlike enzymes and the chemicals they have evolved to recognize, odors and their receptors are not specifically matched to each other. The body creates a spectrum of different receptor types in the nose (or antenna, if you’re an insect or crustacean) and then tries to make sense of how the odors it happens to encounter stimulate those receptors.
Even a simple, molecular odorant, then, will likely interact with more than one receptor — it’s the range and intensity of interactions that mark each odorant. So, complex smells, made up of dozens or hundreds of odorants, wind up being a smear of overlapped spectra of their different components. In the simplest formulation, say odorant A tweaks the spectrum of receptors like this:
Well, if you combine A and B into one complex smell, you get:
Which, it isn’t hard to see, is a combination of odorants A and B. This is what smell researchers call elemental processing — because the elements of the complex smell are still there and identifiable when you look at the higher-level perception. For a real-life example, think of smelling apple pie, but being able to smell the apples and cinnamon as separate components of the smell.
It gets more complicated when you have two odorants, A and A′, that smell similar to each other. If A′ looks like:
Then the combination of A and A′ will look something like:
If the code were this simple, you’d already have a mishmash that wouldn’t allow you to tell whether A and A′ were both there, or you just had a lot of either A or A′ alone. But it gets even more complicated, because similar odorants actually interfere with each other. The resulting perception actually looks more like:
So that, not only can’t you recognize that the A and A′ patterns are there, you actually start getting something that doesn’t look much like either one. This is called configural processing, in which the combination of two similar smells actually smells different than either does separately, and there’s no way of picking out components. This one is harder to give an example for, but one (possibly stretched) example would be how, on different people’s skin, the same cologne starts to smell very differently.
So that’s been the given wisdom: similar smells undergo configural processing to create utterly new sensations; different smells undergo elemental processing and retain their character. It was simple, clear, and explained a lot of what people were seeing in lab experiments with organisms as different as insects, fish, and mammals.
In retrospect, it almost had to be wrong.
Enter Mssr. Frederick & associates of the fine metropolis and University of Chicago, who’ve put yet another nail into the coffin of the simple configural/elemental duality. They did this by showing how a series of odorant pairs, selected so that both their subjective sensations and the pattern of glomeruli they activate in the rat olfactory bulb differ incrementally, don’t follow the pattern at all.
Briefly, they chose a bunch of odorants ranging from the indistinguishable — (+)- vs. (–)-limonene (orange smell) — to the very different hexanal (green, leafy smell) vs. ethylbenzene (gasoline smell) — and checked to see whether a rat trained to recognize the combined odorants could then recognize the components. Things just about immediately went wrong with the configural/elemental hypothesis, with rats recognizing the (+,–)-limonene mixture elementally — in other words, the mixture and the components looked the same, once you corrected for differences in intensity.
Still, that one was slippery — if the two versions of limonene were truly indistinguishable, they might not actually represent different odors.  You wouldn’t expect an odorant to interfere with itself.  The hexanal/ethyl benzene combination was more interesting along these lines, since you’d expect the two very different smells to maintain their character in the mixture. Once again, the simple expectation was wrong: rats trained on the mixture recognized hexanal, but not ethyl benzene. Similar to the group’s earlier paper, they were seeing overshadowing processing, in which one component effectively masked the other. They got the same result with the similarly mismatched odorant pair of isoamyl butyrate (fruity/banana) and butyric acid (depending on context, either sharp cheese or sour/nasty). If you plot the similarity of their odorant pairs to the results they saw, you get no significant pattern.
So where does that leave us? Well, as the researchers point out, nowhere is it written in stone that dissimilar odors can’t interfere with each other, at some point in the chain of events from receptor to higher-brain perception. In addition, the configural/elemental hypothesis had come from a limited data set of not-completely defined odorants. In particular, the fact that the current study is based on the extent to which the odorants they’re working with affect differently the smell-routing center of the brain is new. It looks like we’re at the beginning of a (possibly long) process to figure out how it all really works.
As with my damned foot, some assembly is going to be required. One week off work, and then the long, semi-mobile Mickey-Mouse-boot recovery period. The aim is, again, to make Fire School in early June. Wish me luck.
 I note this only because, thinking about it, it seems logical that a female surgeon might attract female residents, surgery still being a bit of a Boy’s Club.
 They’re going to start thinking I’m some kind of groupie, but the fact is this paper caught my eye before I saw the authors.
 I’m skipping over a world of possible significance here: on a purely theoretical basis, two mirror-image isomers like (+)- and (–)-limonene should not smell the same. Look to a soon-to-come blog about isomers and the vibration theory of smell for the missing detail. For the present, let’s just accept that they’re virtually indistinguishable smells.
 Nothing if not thorough, they actually tested whether (+)-limonene could interfere with its own odor — and excepting a little statistical noise, it didn’t.
Sunday, April 5, 2009
We Who Are About to Be Butterflied ...
Not a growth on the foot, as I thought myself, but a malformation of the bones behind the big toes, bunions make it impossible for the first phalanges (toebones of the big toes) to slide atop the metatarsals when the heel comes up. What that means in practical terms is that your big toes have a click that hurts like the bejezzus when you try to walk (not fun for XC skiing, either). For anybody, that would be a problem that might make one consider surgery; for a dog handler who needs to be able to walk and walk, and who’s already done the medical treatment bit for his lower back and left knee ...
Well, I always said I wouldn’t go for surgery if I had a choice. My only other choice is to lose my ability to field with a dog in a few years.
Anyhow, partly because of new techniques and partly because my own case isn’t yet extreme, my doc is at the moment only anticipating three days on crutches (though she says some patients stay on the crutches a few days longer because it’s more comfortable). After that, six to eight weeks in Mickey Mouse boots, but more-or-less mobile. Obviously I’ll be a base camp weenie at any searches that come up before mid- to late-May. Target, which doc thinks is reasonable, is going to Fire School early June, and a normal summer. Wish me luck.
In the meantime, I’ve run out of time to write my usual blog tonight, though if next week goes well enough, I may have some time to do a post — though I’m only supposed to be on crutches for three days, it’s Vicodin for the first week, so I’m not doing any driving and am taking the week off. Hopefully I won’t be too much of a crybaby, or too zonked out, to post on an interesting finding on the code that helps the nose identify the components of a complex smell — or not.