0:11 The fragrance that you will smell, you will never be able to smell this way again. It’s a fragrance called Beyond Paradise, which you can find in any store in the nation. Except here it’s been split up in parts by Estée Lauder and by the perfumer who did it, Calice Becker, and I’m most grateful to them for this. And it’s been split up in successive bits and a chord.
0:33 So what you’re smelling now is the top note. And then will come what they call the heart, the lush heart note. I will show it to you. The Eden top note is named after the Eden Project in the U.K.
0:45 The lush heart note, Melaleuca bark note — which does not contain any Melaleuca bark, because it’s totally forbidden.
0:53 And after that, the complete fragrance. Now what you are smelling is a combination of — I asked how many molecules there were in there, and nobody would tell me. So I put it through a G.C., a Gas Chromatograph that I have in my office, and it’s about 400. So what you’re smelling is several hundred molecules floating through the air, hitting your nose.
1:17 And do not get the impression that this is very subjective. You are all smelling pretty much the same thing, OK? Smell has this reputation of being somewhat different for each person. It’s not really true. And perfumery shows you that can’t be true, because if it were like that it wouldn’t be an art, OK?
1:38 Now, while the smell wafts over you, let me tell you the history of an idea. Everything that you’re smelling in here is made up of atoms that come from what I call the Upper East Side of the periodic table — a nice, safe neighborhood. (Laughter) You really don’t want to leave it if you want to have a career in perfumery. Some people have tried in the 1920s to add things from the bad parts, and it didn’t really work.
2:04 These are the five atoms from which just about everything that you’re going to smell in real life, from coffee to fragrance, are made of. The top note that you smelled at the very beginning, the cut-grass green, what we call in perfumery — they’re weird terms — and this would be called a green note, because it smells of something green, like cut grass.
2:22 This is cis-3-hexene-1-ol. And I had to learn chemistry on the fly in the last three years. A very expensive high school chemistry education. This has six carbon atoms, so “hexa,” hexene-1-ol. It has one double bond, it has an alcohol on the end, so it’s “ol,” and that’s why they call it cis-3-hexene-1-ol. Once you figure this out, you can really impress people at parties.
2:49 This smells of cut grass. Now, this is the skeleton of the molecule. If you dress it up with atoms, hydrogen atoms — that’s what it looks like when you have it on your computer — but actually it’s sort of more like this, in the sense that the atoms have a certain sphere that you cannot penetrate. They repel.
3:05 OK, now. Why does this thing smell of cut grass, OK? Why doesn’t it smell of potatoes or violets? Well, there are really two theories. But the first theory is: it must be the shape. And that’s a perfectly reasonable theory in the sense that almost everything else in biology works by shape. Enzymes that chew things up, antibodies, it’s all, you know, the fit between a protein and whatever it is grabbing, in this case a smell. And I will try and explain to you what’s wrong with this notion.
3:38 And the other theory is that we smell molecular vibrations. Now, this is a totally insane idea. And when I first came across it in the early ’90s, I thought my predecessor, Malcolm Dyson and Bob Wright, had really taken leave of their senses, and I’ll explain to you why this was the case. However, I came to realize gradually that they may be right — and I have to convince all my colleagues that this is so, but I’m working on it.
3:59 Here’s how shape works in normal receptors. You have a molecule coming in, it gets into the protein, which is schematic here, and it causes this thing to switch, to turn, to move in some way by binding in certain parts. And the attraction, the forces, between the molecule and the protein cause the motion. This is a shape-based idea.
4:26 Now, what’s wrong with shape is summarized in this slide. The way –I expect everybody to memorize these compounds. This is one page of work from a chemist’s workbook, OK? Working for a fragrance company. He’s making 45 molecules, and he’s looking for a sandalwood, something that smells of sandalwood. Because there’s a lot of money in sandalwoods. And of these 45 molecules, only 4629 actually smells of sandalwood. And he puts an exclamation mark, OK? This is an awful lot of work. This actually is roughly, in man-years of work, 200,000 dollars roughly, if you keep them on the low salaries with no benefits. So this is a profoundly inefficient process. And my definition of a theory is, it’s not just something that you teach people; it’s labor saving. A theory is something that enables you to do less work. I love the idea of doing less work. So let me explain to you why — a very simple fact that tells you why this shape theory really does not work very well.
5:28 This is cis-3-hexene-1-ol. It smells of cut grass. This is cis-3-hexene-1-thiol, and this smells of rotten eggs, OK? Now, you will have noticed that vodka never smells of rotten eggs. If it does, you put the glass down, you go to a different bar. This is — in other words, we never get the O-H — we never mistake it for an S-H, OK? Like, at no concentration, even pure, you know, if you smelt pure ethanol, it doesn’t smell of rotten eggs. Conversely, there is no concentration at which the sulfur compound will smell like vodka. It’s very hard to explain this by molecular recognition. Now, I showed this to a physicist friend of mine who has a profound distaste for biology, and he says, “That’s easy! The things are a different color!” (Laughter)
6:25 We have to go a little beyond that. Now let me explain why vibrational theory has some sort of interest in it. These molecules, as you saw in the beginning, the building blocks had springs connecting them to each other. In fact, molecules are able to vibrate at a set of frequencies which are very specific for each molecule and for the bonds connecting them.
6:43 So this is the sound of the O-H stretch, translated into the audible range. S-H, quite a different frequency. Now, this is kind of interesting, because it tells you that you should be looking for a particular fact, which is this: nothing in the world smells like rotten eggs except S-H, OK?
7:05 Now, Fact B: nothing in the world has that frequency except S-H. If you look on this, imagine a piano keyboard. The S-H stretch is in the middle of a part of the keyboard that has been, so to speak, damaged, and there are no neighboring notes, nothing is close to it. You have a unique smell, a unique vibration.
7:25 So I went searching when I started in this game to convince myself that there was any degree of plausibility to this whole crazy story. I went searching for a type of molecule, any molecule, that would have that vibration and that — the obvious prediction was that it should absolutely smell of sulfur. If it didn’t, the whole idea was toast, and I might as well move on to other things.
7:48 Now, after searching high and low for several months, I discovered that there was a type of molecule called a Borane which has exactly the same vibration. Now the good news is, Boranes you can get hold of. The bad news is they’re rocket fuels. Most of them explode spontaneously in contact with air, and when you call up the companies, they only give you minimum ten tons, OK? (Laughter) So this was not what they call a laboratory-scale experiment, and they wouldn’t have liked it at my college.
8:20 However, I managed to get a hold of a Borane eventually, and here is the beast. And it really does have the same — if you calculate, if you measure the vibrational frequencies, they are the same as S-H.
8:34 Now, does it smell of sulfur? Well, if you go back in the literature, there’s a man who knew more about Boranes than anyone alive then or since, Alfred Stock, he synthesized all of them. And in an enormous 40-page paper in German he says, at one point — my wife is German and she translated it for me — and at one point he says, “ganz widerlich Geruch,” an “absolutely repulsive smell,” which is good. Reminiscent of hydrogen sulfide. So this fact that Boranes smell of sulfur had been known since 1910, and utterly forgotten until 1997, 1998.
9:14 Now, the slight fly in the ointment is this: that if we smell molecular vibrations, we must have a spectroscope in our nose. Now, this is a spectroscope, OK, on my laboratory bench. And it’s fair to say that if you look up somebody’s nose, you’re unlikely to see anything resembling this. And this is the main objection to the theory.
9:35 OK, great, we smell vibrations. How? All right? Now when people ask this kind of question, they neglect something, which is that physicists are really clever, unlike biologists. (Laughter) This is a joke. I’m a biologist, OK? So it’s a joke against myself.
9:52 Bob Jacklovich and John Lamb at Ford Motor Company, in the days when Ford Motor was spending vast amounts of money on fundamental research, discovered a way to build a spectroscope that was intrinsically nano-scale. In other words, no mirrors, no lasers, no prisms, no nonsense, just a tiny device, and he built this device. And this device uses electron tunneling. Now, I could do the dance of electron tunneling, but I’ve done a video instead, which is much more interesting. Here’s how it works.
10:21 Electrons are fuzzy creatures, and they can jump across gaps, but only at equal energy. If the energy differs, they can’t jump. Unlike us, they won’t fall off the cliff. OK. Now. If something absorbs the energy, the electron can travel. So here you have a system, you have something — and there’s plenty of that stuff in biology — some substance giving an electron, and the electron tries to jump, and only when a molecule comes along that has the right vibration does the reaction happen, OK? This is the basis for the device that these two guys at Ford built.
10:58 And every single part of this mechanism is actually plausible in biology. In other words, I’ve taken off-the-shelf components, and I’ve made a spectroscope. What’s nice about this idea, if you have a philosophical bent of mind, is that then it tells you that the nose, the ear and the eye are all vibrational senses. Of course, it doesn’t matter, because it could also be that they’re not. But it has a certain — (Laughter) — it has a certain ring to it which is attractive to people who read too much 19th-century German literature.
11:32 And then a magnificent thing happened: I left academia and joined the real world of business, and a company was created around my ideas to make new molecules using my method, along the lines of, let’s put someone else’s money where your mouth is. And one of the first things that happened was we started going around to fragrance companies asking for what they needed, because, of course, if you could calculate smell, you don’t need chemists. You need a computer, a Mac will do it, if you know how to program the thing right, OK? So you can try a thousand molecules, you can try ten thousand molecules in a weekend, and then you only tell the chemists to make the right one. And so that’s a direct path to making new odorants.
12:19 And one of the first things that happened was we went to see some perfumers in France — and here’s where I do my Charles Fleischer impression — and one of them says, “You cannot make a coumarin.” He says to me, “I bet you cannot make a coumarin.”
12:31 Now, coumarin is a very common thing, a material, in fragrance which is derived from a bean that comes from South America. And it is the classic synthetic aroma chemical, OK? It’s the molecule that has made men’s fragrances smell the way they do since 1881, to be exact.
12:49 And the problem is it’s a carcinogen. So nobody likes particularly to — you know, aftershave with carcinogens. (Laughter) There are some reckless people, but it’s not worth it, OK?
13:03 So they asked us to make a new coumarin. And so we started doing calculations. And the first thing you do is you calculate the vibrational spectrum of coumarin, and you smooth it out, so that you have a nice picture of what the sort of chord, so to speak, of coumarin is. And then you start cranking the computer to find other molecules, related or unrelated, that have the same vibrations.
13:27 And we actually, in this case, I’m sorry to say, it happened — it was serendipitous. Because I got a phone call from our chief chemist and he said, look, I’ve just found this such a beautiful reaction, that even if this compound doesn’t smell of coumarin, I want to do it, it’s just such a nifty, one step — I mean, chemists have weird minds — one step, 90 percent yield, you know, and you get this lovely crystalline compound. Let us try it.
13:54 And I said, first of all, let me do the calculation on that compound, bottom right, which is related to coumarin, but has an extra pentagon inserted into the molecule. Calculate the vibrations, the purple spectrum is that new fellow, the white one is the old one. And the prediction is it should smell of coumarin. They made it … and it smelled exactly like coumarin. And this is our new baby, called tonkene. You see, when you’re a scientist, you’re always selling ideas. And people are very resistant to ideas, and rightly so. Why should new ideas be accepted? But when you put a little 10-gram vial on the table in front of perfumers and it smells like coumarin, and it isn’t coumarin, and you’ve found it in three weeks, this focuses everybody’s mind wonderfully. (Laughter) (Applause)
14:55 And people often ask me, is your theory accepted? And I said, well, by whom? I mean most, you know — there’s three attitudes: You’re right, and I don’t know why, which is the most rational one at this point. You’re right, and I don’t care how you do it, in a sense; you bring me the molecules, you know. And: You’re completely wrong, and I’m sure you’re completely wrong.
15:16 OK? Now, we’re dealing with people who only want results, and this is the commercial world. And they tell us that even if we do it by astrology, they’re happy. But we’re not actually doing it by astrology. But for the last three years, I’ve had what I consider to be the best job in the entire universe, which is to put my hobby — which is, you know, fragrance and all the magnificent things — plus a little bit of biophysics, a small amount of self-taught chemistry at the service of something that actually works.
15:45 Thank you very much. (Applause)