Best of NG - Genes and Smells

We all know the old joke - my dog’s got no nose! How does he smell? Terrible! And it’s time for a whiff of nostalgia from February 2014.
03 January 2016

Interview with 

Stuart Firestein, Columbia University


A dog's nose


Kat:: But first, it's time for a whiff of nostalgia from February 2014. Cheesy jokes aside, smell is one of the keys ways humans and other animals sense the world around them. Stuart Firestein, Professor of Biology at Columbia University in New York explained to me how our sense of smell works, and why it's so important.

Stuart -   So it's quite a remarkable sense to begin with.  One that in humans, we underestimate.  There's generally this idea, I think, that people have less of a sense of smell or less dependence on smell than many other animals, that were not as good at it. Actually, that's not quite true.  We're quite good at smell.  When you test this carefully, the biggest problem with our sense of smell it turns out, in fact, is that we walk on two legs, so our noses are about five feet up in the air here and all the good odours are down within a few inches to the ground.  That's why dogs put their nose right to the ground when they catch a scent. 

But you know that we have a very good sense of smell because we use it in the sense of flavour, which is different from taste, sweet, sour, salt, bitter, but everything else is flavour and that's about 80% olfaction. And that's because when we put food in our mouth and we crush it, we send it up what's called retronasal pathway, the back of our throat, where it impinges very closely now on the olfactory receptors which are in our nose.

Kat -   And what do we know about these olfactory receptors?  How do they work?  And what genes are involved in the sense of smell?

Stuart -   Yes, they're quite remarkable as it turns out as well.  So first of all, we smell a large number of molecules - hundreds of thousands conceivably.  I mean, we know of many, many thousands and then there are new smells that pop up every day, you know, like, new car smell. I mean, it's a very clear smell, but we clearly haven't evolved something for that, so we can put blends together.  So there are many, many smells.  They're all small organic molecules. 

And there are now a large number of receptors - these are these little proteins that sit in the membranes of the sensory neurons that are way up in the top of our nose.  Those sensory neurons have these proteins in their membrane that bind to these odours much like a lock and a key mechanism, and then when they bind to these receptor, it depolarizes the cell, which they changes the cell's voltage, electrical characteristic, and that signals the brain that this receptor has located a particular molecule which is now an odour.  And the brain somehow or another now interprets that to be a banana or a pear or a pile of dung or whatever it might be that the chemical is coming from. 

The receptors themselves were first discovered as a large gene family by Linda Buck and what was remarkable about the discovery that made it worth the Nobel Prize perhaps is that it turns out to be an extremely large family of genes.  Indeed, the largest family of genes in our genome.

Kat -   How many are we talking about here?

Stuart -   Well, so in most mammals, we're talking about something in the range of a thousand genes.  To put that in some perspective, we now think having sequenced the whole human genome that the typical mammalian genome is maybe 25,000 genes.  So now, a thousand of them are devoted to your schnozzola here, your nose, you know, that's remarkable.  That's 2 per cent of your genome, between 2 and 5 per cent of your genome devoted to your nose.  So in humans, it's a little bit lower in number.  We actually have the thousand genes in our genome, but about half of them seem to be what we call pseudogenes, which means they've mutated in such a way that they are no longer, probably capable of making a functional protein, and so we get by on, let's say 500.  And the next largest family of these receptors are the ones for serotonin, very important to psychological illnesses and things like that.  And in the serotonin family there are 15 genes.

Kat -   Wow!

Stuart -   So compared to 500 for odour receptors or a thousand if you're a mouse.

Kat -    So, what do we know about how cells in the nose choose which odour receptor that they're going to go with?  How do they choose which one to switch on?

Stuart -   Yes.  This is probably the biggest question in the field right now.  It's a remarkable observation that we know, but we have no idea what the mechanism is. So the observation is that each sensory neuron - you have about 10 million of them in this little tissue at the top of your nose - each one of these sensory neurons goes through the genome somehow and picks one of those genes and all of the proteins that it makes, which are millions of receptors are made from that one gene. 

So, each cell is devoted to one particular receptor and therefore one set of odours, whatever odours that receptor binds.  Not only are they - we say then monogenic, that they've picked on gene from, let's say the thousand possible genes that are spread all over the chromosomes.  They're located on virtually every chromosome.  So somehow or another, the cell has picked one gene.  It's remarkable that mistakes don't seem to get made.  I mean, a cell really does seem to pick this one gene and express all of its receptors off of that gene for its entire lifetime.

Kat -   What do we know so far about what's controlling that choice and how these decisions are made and how the genes are picked and switched on?

Stuart -   Almost nothing.  Actually, I could say nothing.  We could leave the almost out.  There have been many theories.  We've tried many things.  Many laboratories have tried many things, but we haven't really got a very good handle yet on precisely what it is that was controlling them.  It's taught to be probably some feedback mechanism.  We do know this: if a cell chooses a pseudo gene one of these genes that's no good, that doesn't make a good protein, it will turn that off and go back and pick another one and then presumably, continue doing that until it finds a gene that makes a good protein and does so. 

So the thought is, well, it must have something to do with the functional protein and then some feedbacks that says to the cell, "Okay, you found a good protein, turn off your gene choice mechanism and stop whatever you're doing, just make this protein."  But we've never found that signal.  So, the answer really is we don't know.  There are lots of ideas, but we still don't know.  It's a big question.

Kat -   It seems a very, very mysterious sense.  What do you still really want to know about it?

Stuart -   Still, there are quite a few mysteries about it, that's true.  We don't know really why it has such a strong effect on memory.  The wiring in the brain is a little bit - is a bit unusual, I will say for a sensory system.  It doesn't go through a piece of the brain called the thalamus, which all other sensory systems do.  We don't know what that means.  I'm just stating a simple anatomical curiosity.  We have no idea if that's meaningful or not meaningful or anything. 

The memory business is quite curious.  It, I should point out that the memories that are revoked by olfaction always have a strong emotional content, so you remember the first day of school or first lover or the last lover, or something like that, you know?  Or you are at grandmom's house, but it's not like you smell something and remember a page of text or an equation or something useful.

Kat -   Unfortunately, yes.

Stuart -   That's right.  That doesn't seem to work, so there are always these emotionally tainted or strongly emotional memories.  Now, we're not quite sure what that means either, but that's an observation that we find with them.  They certainly govern a great deal of our feelings about things in very subtle ways often.  I mean, people are always interested in pheromones and things like that, something you can spritz on yourself and you'll become super attractive. 

But I will say, for example, that olfaction can have very strong negative effects in interpersonal relation.  So you can meet somebody, find them quite attractive physically.  Then you talk to them and now they're even more attractive intellectually and socially and all the rest of that.  And then you finally, kind of, get up close to them, you know, for the first kiss or something and they have some off odour and that's it.

Kat -   Yes.

Stuart -   It's over, right?  And you'll never get past that.

Kat -   Yes.

Stuart -   I don't know care how good all the rest of the stuff is, you just won't get past that.  So we're very strongly attuned to that sort of thing, for sure.

Kat -   That's what you'd like to unravel, the scent of a woman.

Stuart -   Yes.  That would be fabulous, and put it in a bottle.



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