Sunday, April 19, 2009

Smoke and Mirrors

Yesterday, coming back from a SAR training [1], we pulled to the side of the road as a fire truck, lit up like Times Square [2], passed by in the opposite diretion. It was my peeps, the tanker truck from my very own substation.

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 [3]. 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 [4]. 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 [5].

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 [6] 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:

You can see how, in a loosey-goosey way, the two look pretty much the same provided they’re rigid; red on one side, blue on the other. But if they start moving, version A looks like this:

While version B looks like:

Now, one is red on one side, blue on the other, and the other is red and blue touching each other. It’s the different motions those two structures can accomplish, rather than their static structures, that the receptor is looking at.

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 [7].

“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 [8]. 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.

[1] Heather taught, I did precious little other than keep a teammate’s pickup truck’s tailgate warm.
[2] 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.
[3] Of course, we could always follow our hose back out — but I’d screwed the pooch on searching the room effectively for our fire.
[4] 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.
[5] Full disclosure, I’ve been fairly dismissive of the vibration theory — one reason being it’s one of those early guesses that were made before we really understood how proteins work. To be fair, it’s gotten some serious scientific argument made in its favor much more recently. But read on, it turns out it may have some currency after all.
[6] I am a true apostate of that school.
[7] All right, stop the snickering.
[8] An application, I believe, of the
Bernoulli principle.

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