Thursday, July 30, 2009

Crowded House

Her name was Janet, and she had impossibly long, brown hair. Cute as all get-out, and smart to boot: she was one of the pack of new graduate students that year at my biochemistry and biophysics program [1]. More importantly, she seemed possibly interested in me — so I asked her out.

That Friday night, I came by her lab — she was doing a rotation with the biophysics group, a cool subspecialty in which people used x-rays to create patterns of dots that computers helped them decode into the shapes and structures of protein molecules [2] — to pick her up. The plan was dinner, maybe a coffee afterward.

But a lab mate of hers invited himself along.

“I can drive,” he said. I can’t remember whether he was a grad student or a postdoctoral fellow, only that he was older than both of us; but since he had the car, I’m thinking postdoc.

I was pissed off. I was also seriously uncertain of the terrain: was he truly trying to horn in? Did anybody have that kind of gall? Or cluelessness? Or had she set it up, to “de-date” the situation? She certainly hadn’t said she didn’t want him along, which didn’t bode well for my prospects. Still, as a matter of philosophy, my ire centered on this guy [3] — competition, OK; but I draw the line at interference.

So we have our “three’s a crowd” date, with increasing comprehension that I wasn’t going to get anywhere here. But lacking a graceful way of bowing out early, I had to follow through, as if everything were cool, with the whole God-damned dinner. I had my pride [4].

Finally, we’re done; we took her home first. I can’t remember why — I may have left my bike there — but I asked him to drop me off back at the lab. He pulls up to the building, and as I open the door and step out, I allow one crack in my “it’s all good” demeanor of the evening [5].

I asked, “Aren’t you going to walk me to the door?”

He turned away for a moment, couldn’t look me in the eye; and for the first time that evening, I found something to like about the guy — at least he had a sense of shame.

As crowded as that date was, it was considerably less so than the vomeronasal organ is turning out to be. This “pheromone sensor” is sometimes in the roof of the mouth, sometimes in the nasal cavity of vertebrates; but it’s absent in humans and great apes.

In the beginning, the concept of the VNO, also known as the Jacobson’s organ, was simple.
We already knew — because we had one — that the olfactory organ conveyed a sense of conscious smell, a flexible and rapid sensor for whatever chemical cues the environment cared to throw at us, which we then could use to craft a flexible, highly situation-specific, and even individualized response.

The VNO, on the other hand, was supposed to be the sensor for a kind of molecular secret code — a species-specific series of chemical communications that were far more specialized, and which elicited hormonal and reflexive actions that didn’t require conscious sensation of the signal.
This picture developed from the situation in insects, in which these chemical signals, called pheromones, were first discovered and studied. One insect creates a pheromone, another member of its species receives it, and that reception causes a characteristic response — whether to court and mate, show aggression, horde up, whatever [6]. Same pheromone, same response, every time.

Mother Nature, though, finds human beings’ need to classify to be utterly and hopelessly quaint. From the beginning, scientists warned us that it might not be that simple in higher organisms. They were right.

For one thing, and I’ll repeat myself here, mammals don’t do anything for just one reason — pheromone signals seem to enter a kind of voting process that takes in a lot of input and tries to create the best possible response. For another, when the lab geeks started picking apart the receptor proteins that served as the chemical sensors of the system, they rapidly found a diversity that hinted at a much more complicated situation.

The first “pheromone receptors,” it turned out, could be split into two families; interestingly, one of them is predominant in one part of the VNO, the other family in the other part. One immediate possibility was that the two parts of the organ essentially fractionated the pheromone molecules, with one set of sensors responding to one type, maybe those that volatilized into the air efficiently, while the other responded to those that didn’t volatilize well and had to enter the organ in a water solution or other liquid form. Without more to go on, a number of other possibilities fit the bill as well.

Then came the news that the VNO also contained receptors that, for all the world, looked like the ones in the olfactory organ. Was the VNO contributing to the conscious sense of smell? Or were the olfactory receptors in the organ allowing molecules that normally acted as conscious odorants convey a reflexive, pheromone-type signal as well? Investigators also discovered a fourth family of receptors, the trace amine-associated receptors, which sense volatile amines — a toxic family of molecules that contribute to the smells of decomposition, old fish, ammonia, and urine, among others. Maybe conveying reflexive aversion to toxins?

As if four weren’t enough of a crowd, today’s paper, from Mssr. Stéphane Rivière at the University of Geneva and buds, reports the discovery of yet another receptor family in the VNO: formyl peptide receptor-like proteins.

Formyl peptide receptors play a very interesting role elsewhere in the body. They help guide white blood cells to the site of an infection, using chemicals associated with pathogens and tissue damage as the cue. The City of Peace Posse tested that idea out, and found out that the genes for these VNO receptors were able to convey the ability to respond to these cues to nerve cells and that the VNO tissues themselves are sensitive to them.

The connections between smell and immunity, once suggested by Lewis Thomas as the scientific equivalent of a “spitball” idea, are getting harder and harder to ignore. Thomas’ pure concept, that the body may have co-opted the immune system to create a sense of smell (or, more likely, the other way around) mostly isn’t true; not only are most of the molecular actors in immunity and smell different, but they generally are different types of molecules with very different mechanisms [7].

Still, the parallels are striking. As we better understand olfactory receptors, they seem less the pat, lock-and-key, one-odorant/one-receptor, enzyme-like sensors we might have expected (though the “original” VNO receptors are, for a number of reasons, exactly that kind of beast) and more like a cloud of molecular recognition hovering in wait of the next odorant, old or novel, to come along. No one receptor “belongs” to, say, the acetic acid molecule that gives vinegar much of its smell; rather, all share varying responsibility for the acid, with a small number vastly better than others. Dogs’ larger repertoire of receptors than humans’ may help give the former a more acute sense of smell not because it detect more odorants per se, but because it’s got more overlapping ability to sense the same potential swarm of odorants, and so tends to do the same job with more sensitivity. That sounds a lot less like enzymes and a lot more like antibodies, the immune system’s way of doing a similar job.

The discovery of the formyl peptide receptors in the VNO immediately suggests two different but very important possible new roles for the organ.

Rodents (the study was in mice) are good at detecting and declining tainted food; rats are legendary in their ability to evade attempts to poison them. The formyl peptide receptors in the VNO could be playing an active role in subverting the animal’s appetite when food is dangerous (along with the trace amine-associated receptors, see above). On the other hand, the chemicals that these receptors detect can be found in a number of secretions, including urine: this may be a system for identifying infected animals of your own species, so you can avoid them.

Which brings us, again, to dogs. Any owner of a pack of them has probably seen how, when one is sick or somehow “not right,” the others may, shattering our boy-scouts-in-fur-coats anthropomorphization, gang up on it and harass it. Well, it now seems very possible that setting up an antagonistic stance toward a sick pack mate is a role of the VNO [8]. Along those same lines, this could be the receptor responsible for the amazing ability of dogs to detect cancerous tissues in humans — an ability whose proponents tend to forget hasn’t been proved to be any more accurate or cost-effective than standard diagnostic methods, but which nevertheless seems real.

’Course, the “all of the above” and “none of the above” possibilities remain in play. The VNO began its conceptual life as a pure mystery; in the absence of data, some folks attributed to it an almost supernatural character. The reality, now that we have the data, is a bit more prosaic, but no less mysterious, and in some ways far more majestic in scope: we have only begun to understand the large number of important functions that this organ plays in social interactions, speciation, and survival.

The naked ape, also, stands awkwardly in the room: we and our close relatives don’t appear to have a VNO, but we do have VNO-like receptors in our olfactory organs. Are any or all of the above playing roles in our unconscious behaviors?

Stay tuned. Sometimes, a crowded house is a good thing.

[1] Long before th’ better half entered the scene. Not that I'm worried about frying pans.
[2] On a topical note, one project they were working on at the time was an ongoing study of the hemagglutinin molecule, the grappling hook that the flu virus uses to gain entry into human cells.
[3] Lest you think I was attributing the worst intent to a well-intentioned but clumsy attempt to cover for a friend who was too timid to say “no,” he did wind up dating her afterward — so the vibe I was getting, that he wasn’t being altruistic, had merit.
[4] Married for 17 years as of last month, I have no further use for pride.
[5] OK, it’s just possible that I was glowering throughout the evening. I attempted the closest I could manage to cool, anyway.
[6] A little more complicated than that, because classically there were “releasing” pheromones, which cause responses, and “primer” pheromones, which set you up for later responses — in the current Wikipedia article, that list has grown to 10 types, plus an “other” category. But the classic view was it was always the same response, and required no more consciousness than is available to a fly.
[7] One important exception: the same proteins that help identify fragments of invading pathogens may also help cherry-pick the odorants that make up our individual body odors.
[8] Again, nothing for just one reason — doubtless visual and behavioral clues play a role as well.


Anonymous said...

Regarding the idea that "smells of decomposition, old fish, ammonia, and urine" may be related to toxin identification - SWEET HOLY FREAKIN' JAYSUS - don't your dogs roll in this kind of stuff? If so, do you think they do it seeking to enrobe themselves in poison? Or is it just an expression of pure joy in enveloping themselves in - well... the pure unholy stink of life itself?

Second regarding the similarities between the immune system and the processes of smell - to me that provides a strong (though I suppose currently unprovable) indication that the areas where they intersect are those that are vitally important. I am, because of my background, prejudiced by the beauty one sees in the parallels between the sciences of electricity, heat transfer and groundwater flow. LaPlace had it right. So freakin' right his beautifully eloquent equations describe an incredible array of natural processes.

Ken Chiacchia said...

Good point, though I'd add to it that different species have very different appropriate reactions to decay -- I don't honestly know a lot about what wild rodents eat, but I do know most canids have some tolerance for eating carrion.

We're also assuming that the stuff the dogs are going for is what smells so offensive to us -- these are complex odors that might have, for example, musk overtones that are what they're after.

On the other hand, I certainly have no idea what role these receptors are playing in the VNO -- only that these types of smells are common to the amines. I was making a pretty broad statement about some very different smells -- the simple urea smell of urine may be unpleasant, but it doesn't bear much resemblance to the polyamine smells of death.

Re. the LaPlace/parallel idea for marking important processes, I certainly wouldn't bet against it.

Anonymous said...

A very belated Happy Anniversary, guys.