Theories of Odorant Structure-Function Relationships: The Future for Designing Fragrance Compounds?

“Perfume is decidedly not about two things: it isn’t about memory and it isn’t about sex. Perfume is about beauty and intellect. A perfume is a message in a bottle—not a smell—and the message is written by the perfumer and read by the person who smells it.”¹

"I think everyone (scientist or not) at some point wonders how smell works. The Italian physicist Giorgio Careri told me that Enrico Fermi in his presence once sniffed the air while frying onions and said “wouldn’t it be nice to know how that works?” I started reading up on smell and it gradually became clear to me that there were big gaps in our knowledge, so I started thinking about it."2

-Luca Turin

Upon getting back into the Chemistry and Technology of Flavors and Fragrances text, I discovered (via Chapter 11) just how much we don't know about how to design odorants. The discovery process of flavor and fragrance molecules throughout history has been haphazard and involving a great deal of luck. The author of this section identifies one of the main methods of finding novel odorants as "Serendipity." While humorous, the fact that scientists consider this a legitimate method for finding new compounds is telling of how little we actually understand the process. It's funny to see how differently contributors to this book speak about our level of understanding of the olfactory system; in this section, internationally recognized biophysicist and perfumer Luca Turin presents two major theories - stress: theories - behind rational odorant design: vibration and shape.

In 1946, Linus Pauling suggested for the first time that the shape of molecules affected their function. This idea has proved to be critical to chemistry but when applied to the flavor and fragrance industry it doesn't always pan out. If the character of odorants relied entirely on their structure they could be designed just like pharmaceuticals. Unfortunately, it's more of a trial-and-error process. In the first place, there's a lack of understanding about the exact structure of olfactory receptors. Receptor antagonists, for example, are important in pharmacology for turning receptors "off." No odorant has been found to do this which means there's something amiss in our comprehension. The olfactory receptors must be somehow different than those that absorb drugs. Additionally, there are a number of  little contingencies like the fact that we can accurately identify functional groups no matter what the rest of the structure looks like. In every case, "rules" about structure-character relationships are broken; catalogues which have tried to place odorants into structural categories are essentially "catalogues of exceptions." 

The counter-theory is that molecules with similarities in vibrational spectra should be similarly perceived by the nose. It should be noted that Turin believed pretty ardently in this theory, even to the point of founding a company called Flexitral, Inc. based on the concept. This theory is supported by evidence of things like boranes and thiols: IR spectra shows that they exhibit the same frequency range and they also smell a lot alike. However, chemically they're completely different…so there's another mystery. Vibration theory only accounts for odorant character so the cause of varying intensity of odorants remains mysterious. Additionally, no one has proven that receptors can respond based on vibrations of molecules and the theory is essentially untested at this point. 

Both theories have their strengths and weaknesses (there's a lot more to them than what I've summarized here). It's possible that human olfaction operates through a combination of both theories, or something altogether different. What was most astounding to me about this chapter is that we understand so poorly something so commonplace yet we're crashing protons together and trying to identify the tiniest bits of matter that seem so distant from our day-to-day reality. That's certainly not to say one area of study is more important than the other, simply that there's an incredible amount that we don't know. With continued research, it's possible we'll find some of the answers right under our noses.

Ashley
1 Suhrawardi, Rebecca. "Style.com/Arabia Pulls Fragrance Legend Luca Turin As Its Fragrance Critic," The Fragrance Foundation Jan 7, 2014. Web. Accessed Oct. 28, 2014.

2 Sinatra, Nina. "Opinion: The Science of Smell; Luca Turin on the Vibration Theory of Scent," The Tech, Online Edition. Massachusetts Institute of Technology: Cambridge, Massachusetts. Apr. 23, 2010. Web. Accessed Oct. 28, 2014. 

3 Rowe, David J (ed.) (2005) Chemistry and Technology of Flavors and Fragrances. Blackwell Publishing: Poole. Ch.11.

Modern Science Writing: A Reflection and Reading Reaction

For this post, I'm going to completely change gears. I've been writing on the Chemistry and Technology of Flavors and Fragrances, but earlier this week I read about a hundred pages from a very different kind of text: The Oxford Book of Modern Science Writing. This book is a collection of extracts, articles, criticisms, poetry, and more from well-known scientists of the twentieth century (everyone from Albert Einstein to Primo Levi), seamed flawlessly together by its editor, Richard Dawkins.

When I finished the last chapter I read ("Who Scientists Are"), and carefully slipped the book back into my bag it felt like one of those moments up to which my whole life has been leading. I've spent a lot of time with my face pressed against textbooks, hoping the knowledge would sort of find its way from the pages through an unknown channel of skin and cell membranes and nerves channels, eventually sticking itself into my memory. I've spent a lot of time wondering why I chose to major in chemistry. What I'm going to do with it, if anything. What I was thinking, if it's worth the stress. If my math skills will inhibit me. If my dreams, as they often have been, will always be bigger than the operating budget and more time-consuming than I can afford.

That said, I've been granted more than my fair share of opportunities. But I've suffered from what I imagine to be a fairly common disillusion about studying science: the idea that learning the secrets of life will be all fireworks and miraculous, Nobel-prize winning discoveries when in reality it takes patience, failure, and compromise. Even though when I set off I knew it would be a difficult path to follow, I didn't comprehend the gaps in knowledge that would cut me off at every turn and have me confused, turned around and frustratingly rummaging in the woods. It seems that after almost three-and-a-half years of studying the subject, I remain hopelessly clueless about it.

Then, there's the whole other branch of that inner argument I mentioned above: I love art in general and poetry in particular. Can those worlds really mesh or will pursuing one inevitably draw me further and further away from the other? Is it a fantasy to think I can do both well?

Here in this book though, the highlighted scientists have an incredible faith in curiosity and the imagination. Many of them - including a number of actual Nobel-prize winners - reflect on their personal difficulties in certain subject areas, their doubts, resource limitations, judgements from others, and more than anything gratitude for what they consider simple good luck (see page 195, Maitland Edey and Donald Johanson's reflection on a chance finding of Lucy in Ethiopia and on page 229 where there's a quote from James Watson, "All through my undergraduate days, I worried that my limited mathematical talents might keep me from being more than a naturalist….there seemed no choice but to tackle my weakness head-on….[math] soon became rather satisfying, even in the age of slide-rules, instead of a source of crippling anxiety").

They have much to say about art. Many of those featured are themselves artists: poetry, short stories, music. Carl Sagan, who I personally admire, wrote spectacular prose (it might make me tear up a little every time I read some). Dawkins says in his introduction to an excerpt from The Demon-Haunted World "open any one of [Sagan's] books and you need go no further than the Table of Contents to experience the tingling of the poetic nerve endings that will continue throughout the book" (239). Just pages before this, before a poem written by Julian Huxley, Dawkins remarks, "I have long thought that science should inspire great poetry, but scientists have published disappointingly few poems" (234).

There are too many great excerpts in this chapter on "Who Scientists Are" to summarize them all, but I figured I could make an attempt to concentrate this book, which is kind of a summary itself, into some of my favorite lines (the most heavily underlined, numerously starred, exclamation point-adorned sentences). One quotation from each of the extracts in this chapter will be listed below. They're words that inspire me, say something I think is really profound, and/or exemplify the kind of person I think I could be (in addition to being quotations able to stand outside the context).

No, I didn't include the authors or the works from which these quotes are specifically excerpted. But as I said, I hope they stand on their own and I hope anyone who reads them says, "wow this book sounds amazing I'm going to go read it." As I prepare to go out "into the real world" with a background in chemistry, a passion for art, and many doubts I can't imagine something better to draw from than a book that, to me, seems like the purpose and justification of science, distilled.

(Page number: "quote.")

156: "Generosity and imagination were, for once, awarded in full. This is a story of human virtue."

161: "How could one seriously believe that the electron really cared about my calculation, one way or the other? And yet the experiments at Columbia showed that it did care…Why it is so, why the electron pays attention to our mathematics, is a mystery that even Einstein could not fathom."

167: "I think we believe that whenever we see an opportunity, we have the duty to work for the growth of that international community of knowledge and understanding…with our colleagues in other lands, with our colleagues in competing, antagonistic, possibly hostile lands…"

171: "She pursued her crystallographic studies, not for the sake of honors, but because this is what she liked to do….at scientific meetings she would seem lost in a dream, until she suddenly came out with some penetrating remark, usually made in a diffident tone of voice, and followed by a little laugh, as if wanting to excuse herself for having put everyone else to shame."

178: "But more incisive than the question, What right have we to form inductions? is the question, How do we form them? [David] Hume gave no explanation of this except habit."

183: "People who write obscurely are either unskilled in writing or up to mischief."

189: "There is poetry in genetics which is more difficult to discern in broken bones, and genes are the only unbroken living thread that weaves back and forth through all those boneyards…it is easy to forget that human fossils remained virtually unnoticed until Darwin."

192: "'It just looked interesting.'" (An archeologist's comment on how he picked the nondescript gully wherein the first Homo erectus fossil was found)

196: "I felt a strong subconscious urge….I am superstitious." (Another archeologist, remarking on the morning of the expedition when the skeleton of Lucy was unearthed)

206: "We who lack an appreciation of history have so little feel for the aggregated importance of small but continuous change scarcely realize that the very ground is being swept from beneath our feet; it is alive and constantly churning."

214: "Suddenly - and how exciting it is when it happens - something will go right and give one a flash of insight into how things work."

219: "There seemed to me an integrity, an essential goodness, about a life in science, a lifelong love affair. I had never given much thought to what I might be when I was 'grown up' - growing up was hardly imaginable - but now I knew: I wanted to be a chemist."

225: "We are coded differently [than social insects], not just for binary choices, go or no-go. We can go four ways at once, depending on how the air feels: go, no-go, but also maybe, plus what the hell let's give it a try. We are in for one surprise after another if we keep at it and keep alive. We can build structures for human society never seen before, thoughts never thought before, music never heard before."

227: "Much better to be the least accomplished chemist in a super chemistry department than the superstar in a less lustrous department."

231: "He gazed at the model, slightly bleary-eyed. All he could manage to say was 'It's beautiful, you see, so beautiful!' But then, of course, it was."

233: "Science often explains the familiar in terms of the unfamiliar." (which is often exactly what poetry does)

237: "In my view, it is the most important function of art and science to awaken this [cosmic religious] feeling and keep it alive in those who are receptive to it."

And finally,

243: "When we shy away from it because it seems too difficult, we surrender the ability to take charge of our future."

On a final note, I started wondering after reading this chapter: at what point can I say that I'm a scientist? Now, I admit that's kind of a fluffy philosophical question. But I was thinking - and maybe this is a product of reading too much Sagan - are we all born scientists, curious about the world and eager to investigate? There's a lot of discussion out there about interest in science waning significantly during adolescence due to poor teaching, peer pressure, and perceived difficulty.
Is the question that should be asked, "at what point is one no longer a scientist?" if the chosen path leads elsewhere? Neil deGrasse Tyson doesn't have a segment in this book but said once - and it's one of my favorite quotations of all time - "In whatever you choose to do, do it because it's hard."

These are the kinds of things I want to keep in mind when taking a terrifying step in life whether that's starting a job, or moving to a new place, or leaving this beautiful little brick bubble.

Ashley

Overview: From Fruit to Flavor

This might sound odd, but I think it would take me a very, very long time to get bored from reading about the development of the flavor industry. This week, I’ve been reading about flavor applications. Everything from the history of the analytical methods used to the gritty technical details of getting the most bang for the bite. As I’ve mentioned previously in this blog, flavors were first commonly synthesized and purified during the mid-nineteenth century, i.e., the Industrial Revolution. However, flavor compounds were not identified and tinkered with by chemists en masse until the invention of gas-chromatography mass-spectrometry (GC-MS) in the 1950’s.

GC-MS Diagram

 Not only did scientists identify and isolate many compounds that they were already peripherally aware of: they also discovered novel flavor and fragrance chemicals, including some of those sensation-causing ones I’ve been rambling on about. Critically, it was determined that flavor is dependent on key aroma compounds - molecules which must be present in order to for a certain taste to result. 

n-decanal

(wikimedia commons)

For example, it was found that n-decanal must be present for an orange to taste like an orange¹.
 Although there are other chemicals present that affect an orange’s flavor, even with their nature-designed uniquely balanced proportions, in the absence of n-decanal an orange just won’t taste right. Pretty nifty. 

In the mid-1970’s, sprectral data from GC-MS was computerized. Yay, digital revolution. Data collection went from counting signals by eye, determining the abundance of signals on UV paper, and comparing the signals present to tabulated collections of compounds. Sounds like not-fun. But it makes me infinitely grateful for the technology I have now. In ten years (or sooner?) we’ll probably be able to tell a computer what was mixed together and under what conditions and the computer output, with a high degree of certainty, what product will be. Until then, we’ll have to work with graphs and charts, albeit digital ones. 

After going through all the fruits and vegetables and whole food natural-type products, flavor companies found the research into new flavor compounds relatively unprofitable. This makes me sad. There was a forray into the flavorful world of common food reactions like fermentation and the Maillard reaction. By 2005, after cataloguing over 2,800 active compounds, the flavor and fragrance companies concluded they should perfect what they have before trying to find more tasty and smelly things. To my chagrin. There is the possibility that mixing and cooking ingredients together produces entirely unrecorded flavor and fragrance compounds but the vast majority of these combinations has not been researched. 

Marie Wright, flavorist, South Brunswick, New Jersey
Wall Street Journal "Creating Portraits"

To manage and master all the compounds we did find out about, the training of Flavorists came on the scene. This is an amazing job and what I want to be when I grow up. Here’s how the making of a flavor/fragrance compound goes: discovery of a compound in nature, perfection of synthetic imitation, painstaking purification, application of creativity to combine flavors in cool new ways, creation of a flavor profile (via an aromagraph), and playing around with the potential uses of the active compound. Upon his visit to Marie Wright's laboratory in New Jersey, Wall Street Journal Photographer Kyoko Hamada remarked: “I had been warned that Marie’s lab might be a bit like Willy Wonka’s Chocolate Factory. Upon entering the lab, we were overwhelmed with the smells of bubble gum, lemon, coffee beans, chocolate, tangerine, and what I’m guessing may have been cupcake, soap, vanilla, banana and amaretto, all mixed together in what was an otherwise very stark and minimal laboratory. It was strange to think that the smells which were so omnipresent in the air were completely invisible to the naked eye….Marie, the flavorist, was a self-assured, charismatic and very charming woman who didn’t dress at all like any scientist I had photographed before. It was great pleasure to meet her and such fun to visit the lab. I am grateful that she didn’t call the Oompa-Loompas when I ended up breaking one of their beakers in all the excitement.²”

Here’s a case study: a European blueberry (billberry) of interest due to its complex taste profile (in contrast to domesticated varieties) was found to contain 132 potential aroma compounds. A complete profile was created of all the aliphatic and aromatic structures, how ripeness affects the the flavor, and how growth location affected chemical composition. Extraction and purification was done using solid-phase micro-extraction (SPME) and analysis was done with GC-MS. Then, the compounds were assigned adjectives like “mint-spicy note” (1-8,cineole) or “flowery-fruity note” (acetate) or “herb-spicy note” (terpinolene). Collecting these results creates a sort of database for the fruit.³ A chemical map.

With enough information and structural alterations, the flavorist can say, “this smells basically like the kind of blueberry I want” as the sniff the mist that sprays out of the GC-MS. Say, a perfect billberry scent. “Now,” says the flavorist, “I’m going to go into the kitchen part of my lab and try it out in a blueberry muffin mix and then eat the muffins” And the processes is repeated until the desired flavor is acheived. 

The problem, as always, is that it’s not that simple. There’s quite the leap from knowing what a food is comprised of and getting those compounds into an applicable form, which is what the rest of the chapter details. 

Therefore, next time: the many, many technical difficulties of actually getting synthetic flavor compounds into food! (And how some very smart people figured out very cool things.) 

In the meantime, enjoy this video on Goldfish Cracker production. It's always fun (scary?) to learn about how our food is made - and to think about all the details they won't include. 

Ashley

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1 Ahmed, E., Dennison, R., Dougherty, R., Richard, H., Shaw, P. “Flavor and odor thresholds in water of selected orange juice components” J. Agr. Food Chem. 26(1) pp.187-91 ^↩


2  Horne, Rebecca. "Favorite 'Creating' Portraits" Wall Street Journal 2011. Accessed 14 Oct. 2014. http://blogs.wsj.com/photojournal/2011/07/18/favorite-creating-portraits/ ^↩

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3  Rohloff, J., Nestby, R., Nes, A., Martinuseen, I. “Volatile Profiles of European Blueberry: Few Major Players, But Complex Aroma Patterns” Latvian Journal of Agronomy. 2009. 12:98-103. ^↩

4 Rowe, David J (ed.) (2005) Chemistry and Technology of Flavors and Fragrances. Blackwell Publishing: Poole. Ch.9.^↩

Sensory compounds are, of course, not limited to cooling and tingling compounds. The breadth of tasteless, odorless chemicals that cause sensation is surprisingly wide and includes chemicals that cause feelings of warmth, pungency, heat, and astringency. Very few synthetic chemicals create the warming and heating sensations. Most of what I'm going to cover in this post comes from things like ginger, Szechuan pepper, chili pepper, mustard, horseradish, wasabi, cloves, and onions.


The first thing you're probably thinking is (maybe): well, warmth and heat are basically the same thing. This is not true in the complex world of sensory compounds. Warming compounds are generally considered to be more gentle (think: the comforting pleasure of vanilla) and heating compounds actually produce their sensation in the form of pain (think: one too many chili peppers). It does get a little confusing here since warm and hot compounds both typically contain "vanillyl moieties." Moiety was a new word for me, too, but it's a just another way to say that there's a structural component that resembles vanillin somewhere in the compound. It seems that the "warm" compounds tend to more closely resemble vanillin than the hot compounds. Most of these chemicals are also oleoresins - another great vocab word - meaning that they are oil-soluble extracts. This makes sense in context with many of the flavor and fragrance molecules being found in the essential oils of plants and naturally their sensory component isn't going to be too far away.

Vanillin
Wikimedia Commons

These warming and heating categories are really cool in all ways but the literal. I've heard a lot of arguments over the years about killing off your taste buds with spicy foods, or whether or not people in Thailand have genes that allow them to eat "Thai Spicy" curry, or if a food actually gets spicier the more of it you eat. Things like that. Science, as it often does, confidently answers these questions.

To answer a few urban unknowns:

Number 1. Desensitization at the nerve level does occur when eating spicy food, that is, something containing anything with a vanillyl moiety which can activate the VR1 or VRL-1 receptors in the mouth. These nerve channels will not activate as readily in a person who eats lots of spicy things compared to a person who does not. In short, no one's "killing their taste buds" with General Tso's Chicken, but they are acquiring something like an immunity to the sensation.

Number 2: This kind of blends into number 1, admittedly, but genetics does give one a sort of pre-determined threshold for spiciness. It's certainly not something that can't be overruled, however, by the above desensitization through regular exposure.

Number 3: Food doesn't technically get any "hotter" the more of it you eat, i.e. the chemicals I'm discussing here won't build on one another's presence. It might feel that the more chili you eat the hotter it gets as a result of repeated exposure to one of these sensory compounds (here, capsaicin) because the nerves simply haven't had time to recover from the prior exposure. Warming and heating compounds will cause the mouth to produce more saliva to "defend" itself against these irritating agents and help the nerves out but sometimes (I'm looking at you, wasabi) it's just not enough.

Hopefully that knowledge gives you a little insight into just how carefully crafted heating and warming compounds are in terms of their being additives in our food. Think about mild, medium, and hot salsas, for instance. Or muscle-warming lotions. Cosmetics are often considered more convincing and desirable from a consumer point of view if the user can feel the effects instantly, such as in products that enhance skin colors, like artificial tans. Maybe something about feeling a warming sensation causes the consumer to associate with lying on the beach? In any case, companies design use these compounds to enhance the flavors and smells of food, gum, mouthwash, lotion, liquor and more.

A kitchen staple? 

A current *hot* area of research, in fact, is finding synergies between these sensory compounds. What cooling, tingling, and warming compounds will enhance one another or create entirely new experiences for the consumer? Takasago International Corporation found that combining vanillin, a cooling agent, gingerone, and capsaicin created cool, warm and tingling effects all at the same time. This patent from von Borstel et al. on creating a better cigarette experience discusses throat feel, mouth sensation, and even reducing the nerve irritation caused by nicotine itself. Although I'm not sure what kind of product outside of cigarettes wouldn't overload one's mouth with all these nerve stimuli - gum, perhaps? - it's not an area of study that's likely to cool off anytime soon.


Ashley



1 Rowe, David J (ed.) (2005) Chemistry and Technology of Flavors and Fragrances. Blackwell Publishing: Poole. Ch.9.^↩