How Sweet It Is!

The title is a (potentially) memorable song by the star of the classic black-and-white sitcom The Honeymooners, Jackie Gleason. The old-timey bickering of Gleason’s character Ralph Kramden, the dated husband-housewife dynamics, and 1950s sensibilities of his show however look young and fresh compared to the long history of artificial sweeteners (yea, check out THAT transition!)

That’s right – these little chemical faux-flavorings have been around for a long time, as has the controversy around their use. Currently only 7 artificial sweeteners are permitted for use in the US (and a slew more of natural non-sucrose sweeteners). Outside the US there are some other legal substances whereas some of ours are banned. I don’t recommend you spend too long thinking about artificial ingredients or else Buzzfeed lists about ’8 Foods We Eat in the US That Are Banned…’ (or 11) will have you drinking water and eating wild berries for the rest of your life.

I don’t want to get embroiled however in the morality of chemical additives, preservatives, GMOs etc, and I want to write this post miles away from considering the biological and moral implications of genetically modified food-stuffs which I find to be a complex and worth-while discussion for another time. My goal here is to provide some salient information about the history and biology of sweeteners. (Full disclosure: History, Biology, and Sugar were my three main passions in high school followed distantly by Athletics and Latin).

The History – Saccharin

So when did it all start for modern sweeteners? It was 1878 when Johns Hopkins-chemist Constantin Fahlberg got home from work and (allegedly) picked up a piece of bread and detected a sweet taste. Depending on the urgency with which you react to such a thing as a chemist, you can imagine Fahlberg exclaiming, “Great Scott, that synthesis today must have yielded a new sugar!” But upon examining his synthesis what he found was, in fact, Ortho sulphobenzamide or saccharin (or to the rest of us, Sweet’n’low).

The chemical and tabletop representation of saccharin.

The chemical and tabletop representation of saccharin.

The impact was obvious – a calorie-free chemical that made anything taste sweet! He applied for patents in NYC in 1884, and eventually moved to Germany where he opened large factories to produce this non-sugar sweetener. Scientific American ran an article on the wonder-chemical in 1886 (see image below). His mentor at JHU, Remsen, who ran the ‘Coal Tar Derivative Analysis Lab’ in which the discovery was made, thought Fahlberg was a criminal who stole the compound, and forever after bitterly called him a scoundrel.

Fahlberg's original findings on Saccharin, published in Scientific American.

Fahlberg’s original findings on Saccharin, published in Scientific American, in the left column.

Food manufacturers began using the product almost instantly, but not many questions were asked until the beginning of the 20th Century. The USDA Director of Chemistry, Harvey Wiley, began one of the first inquiries into the compound. He found the compound, “injurious to health” and he brought the matter to then President Teddy Roosevelt. Roosevelt was in fact was a great consumer of artificial sweetener and did not respond well to the news. When Wiley suggested the only reason Roosevelt had been introduced to the compound was because his physician thought the risk of diabetes was greater than the risk of saccharin, Roosevelt roared back, “Anybody who says saccharin is injurious to health is an idiot.” This statement not only ended Wiley’s career, but also set saccharin aside as a popular food additive and sweetener for the next 100 years (not without some objections – health organizations conducted many more studies and inquiries, and enacted bans, regulations, and advisories several times as in 1911 (described above), 1948 and 1972, ultimately to remove regulation and allow its use widely.  It was banned in California until 2001).

Recent News

So your Facebook’s might have featured some more sensationalized headlines referring to a journal Nature paper released in September discussing the effects saccharin has on gut microbiota and the resulting health effects.  These kinds of studies aren’t new: this one is akin to the papers that came out in the late ’60s, and have been continued consistently since.  In 2008 a very similar study was published discussing sucralose (described next week) the sweetener in Splenda.  The results were:

Evidence indicates that a 12-wk administration of Splenda exerted numerous adverse effects, including (1) reduction in beneficial fecal microflora, (2) increased fecal pH, and (3) enhanced expression levels of P-gp, CYP3A4, and CYP2D1, which are known to limit the bioavailability of orally administered drugs.

– Abou-Donia et al. Journal of Toxicology and Environmental Health

The study this year described how saccharin could similarly alter gut microbiota. They found:

…that consumption of commonly used NAS [non-caloric artificial sweetener] formulations drives the development of glucose intolerance through (…) alterations to the intestinal microbiota.  These NAS-mediated deleterious metabolic effects are abrogated by antibiotic treatment.  Collectively, our results link NAS consumption, dysbiosis and metabolic abnormalities.

– Suez et al. Nature

These results are troubling to say the least, and they certainly warrant a closer look at these chemicals many of us so readily ingest.  The caveat with these studies is often dosage.  The FDA finds a certain acceptable daily intake (usually in mg chemical per kg-body-weight), and these studies show risk at or around that intake.  However, to actually consume even close to that much sweetener would typically require excessive consumption such that, while not impossible, most people would never approach that level.

So there may be harm in these chemicals, but possibly not at the enrichment most of us will experience.  I’ll leave that conclusion tediously there for later posts (or podcasts)  in order to move on to the function and mechanism of sweeteners.

Saccharine making its way into pop culture.  While it's still unclear what is entailed in 'being played like saccharine' Jay-Z is having none of it!

Saccharine making its way into pop culture. While it’s still unclear what is entailed in ‘being played like saccharine’ Jay-Z is having none of it!

The Low-Fat Pack

Saccharin is now the third most popular artificial sweetener in the US. Ahead of it are aspartame and sucralose. Following it are stevia, neotame, acesulfame potassium and advantame.   I’ll go through them one by one next week explaining chemically and functionally how they differ.  But the one thing they all do the same is induce the perception of sweetness.
HowSweet5How Do All These Different Chemicals Do the Same Thing as Sugar?
[Warning: This Section contains words and phrases associated with biochemistry – tread lightly]

So I’ve given you a lot of the history but only a little of the chemistry. Here’s just a sprinkling of the biochemistry involved in the very tricky process of taste. First, sweetness is a broad class of taste – it isn’t specific really, but it defines a general quality of a food. Sweetness receptors (proteins on the surface of your tongue that bind to and react to flavoring agents) are almost a million times less sensitive than bitterness receptors. The theory behind this this: even a little bit of a bitter toxin could kill you, but early man wanted to operate on the higher side of the energetic/caloric scale. So little vs. no bitterness was critical, but early man benefited more by being more sensitive to “a lot” vs. “a whole freaking lot” of sugar and calories.

A 2002 paper from the Proceedings of the National Academy of Science indicated for the first time a specific receptor associated with sweetness. It is in fact a complex of two related receptors (T1R2 and T1R3) which act through G protein signaling and induce the transmission of information to neurons, flavor glomeruli, and the brain. Other studies show that while humans and old-world apes find aspartame sweet, new world apes don’t at all. Likewise, cats lack the T1R protein family and can’t taste sweetness ever (hence their bitter, miserable attitudes…sorry cat lovers, I don’t mean your cats).

Some flavorants may activate different receptors, which can lead to different taste perceptions or mixed taste perception.

Some flavorants may activate different receptors, which can lead to different taste perceptions or mixed taste perception.

The theory of how artificial sweeteners work has evolved with time. In 1914 it was noted that sweet-tasting chemicals had a commonality in small size, hydroxyl groups, and usually a chlorine. Not until 1963 were solid parameters applied with the AH-B theory (a hydrogen donor must be 3nm away from a Lewis base group to interact with the receptor), and then in 1972 the BX theory, confirming the AH-B requirement but stipulating that near the base must also be a hydrophobic group to fit groove in the receptor pocket and improve binding affinity of the chemical ligand to the biological receptor.

Finally, in 2008, the Multipoint Attachment Theory was put forth identifying 8 sites with specific criteria, all set distances apart. While any combination of less than the 8 sites could also bind the receptor and elicit a response, certain sites were weighted more heavily and incorporating all 8 would be ideal. Hence, lugduname was created – a synthetic chemical 225,000x sweeter than sucrose. Flavor testing is another cool topic I might get into one day when I blog about the great Pepsi contract science scandal!

There is also the idea that sugar and sweeteners work in parallel but different pathways. For a detailed look at how sweet taste perception works, check out this link.

One theory of slightly different activation leading to a similar response.

One theory of slightly different activation leading to a similar response.

Finally, most sweeteners are not metabolized but pass right through your body without interacting with anything (allegedly) and thus are ‘calorie free.’  Because they are so potent though, these chemicals are used at much lower concentrations so there is less of a given sweetener than there would be of sucrose to achieve the same sweetness.

If all this has whet your appetite then you’ll be happy to check in next week when I wrap up this sweet science post with part II of How Sweet It Is with a who’s who of sugar substitutes.


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