# There is way too much serendipity

*Crossposted from* [*substack*](https://malmesbury.substack.com/p/there-is-way-too-much-serendipity)*.*

As we all know, sugar is sweet and so are the [$30B in yearly revenue](https://www.statista.com/statistics/1201648/revenue-artificial-sweetener-market-worldwide/) from the artificial sweetener industry.

Four billion years of evolution endowed our brains with a simple, straightforward mechanism to make sure we occasionally get an energy refuel so we can continue the foraging a little longer, and *of course* we are completely ignoring the instructions and spend billions on fake fuel that doesn’t actually grant any energy. A classic case of the Human Alignment Problem.

If we’re going to break our conditioning anyway, where do we start? How do you even come up with a new artificial sweetener? I’ve been wondering about this, because it’s not obvious to me how you would figure out what is sweet and what is not.

Look at sucrose and aspartame side by side:

![Molecular structures of sucrose and aspartame, looking very different](https://substackcdn.com/image/fetch/w_1456,c_limit,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fsubstack-post-media.s3.amazonaws.com%2Fpublic%2Fimages%2F9bc9e0ba-5003-4234-a7a2-23c355b4d612_718x232.png)

I can’t imagine someone looking at these two molecules and thinking “surely they taste the same”. Most sweeteners were discovered in the 20th century, before [high-throughput screening](https://en.wikipedia.org/wiki/High-throughput_screening) was available. So how did they proceed?

Let’s look into these molecules’ origin stories.

[Aspartame](https://en.wikipedia.org/wiki/Aspartame) was discovered accidentally by a chemist researching a completely unrelated topic. At some point, he licked his finger to grab a piece of paper and noticed a strong sweet taste.

[Cyclamate](https://en.wikipedia.org/wiki/Cyclamate) was discovered by a grad student who put his cigarette on his bench, then smoked it again and noticed the cigarette was sweet.

(I know what you’re thinking. The kind of guy who lights up cigarettes in a chemistry lab and places them in the middle of uncharacterised compounds before taking them to his mouth again, must have died young of an interesting death. I checked – he proceeded to live to the old age of 87.)

[Saccharine](https://www.theatlantic.com/technology/archive/2014/10/what-happens-when-chemists-dont-wash-their-hands/381587/) was discovered by a researcher who ate bread without washing his hands and noticed the bread was sweet.

[Acesulfame K](https://en.wikipedia.org/wiki/Acesulfame_potassium) was also discovered serendipitously by a chemist licking his fingers, although the legends don’t specify the exact circumstances behind the finger-licking.

There’s an exception: [sucralose](https://en.wikipedia.org/wiki/Sucralose) was actually the fruit of rational, deliberate design. The researchers reasoned that, if you do slight modifications to sucrose, you could find a molecule that is no longer metabolized but still activates the sweetness receptors. So they started from the formula for sucrose, then made carefully-designed chemical modifications to the structure until –

Haha, just kidding:

*While researching novel uses of sucrose and its synthetic derivatives, Phadnis was told to "test" a chlorinated sugar compound. According to an anecdotal account, Phadnis thought Hough asked him to "taste" it, so he did and found the compound to be exceptionally sweet.*

It is therefore a fact of the world that virtually all the popular synthetic sweeteners were discovered accidentally by chemists randomly eating their research topic.[^oe6rv0gafjc]

I think this is a suspiciously high amount of serendipity. I see two options:

Super-sweet molecules like aspartame are commonplace – there are plenty of molecules hundreds of times sweeter than sucrose, but we only know the few that were ingested by accident,

Super-sweet molecules are very rare, it’s just that chemists accidentally taste *a lot* of chemicals. Entire chemistry departments routinely taste the entire space of possible molecules, but they don’t notice unless the molecule has a strong taste.

To get an idea of how often chemists taste the chemicals they are working with, let’s consider how often a molecule taken at random will taste sweet. That’s equivalent to asking: how specific are our sweet taste receptors?

Low-hanging fruits
==================

Why do we have sweet receptors in the first place?

I thought that we craved sugars so much because of their energy content – if we eat plants that contain a lot of sugars, we can break them down into glucose and use it for metabolism. [This paper from 1989](https://doi.org/10.1016/s0149-7634(05)80213-1) destroys this view: for instance, the sweetness of a sugar molecule isn’t a good indicator of its energy content:

![Table showing the energy content vs sweetness of sucrose, glucose and fructose](https://substackcdn.com/image/fetch/w_1456,c_limit,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fsubstack-post-media.s3.amazonaws.com%2Fpublic%2Fimages%2Fe525aab6-bee5-480c-a947-1b9be81a9d5f_649x277.png)

No alpha in sucrose

And the fruits that taste the best tend to be the least nutritive ones! Also, [before selection by humans](https://hyperallergic.com/226096/the-evolution-of-the-watermelon-captured-in-still-lifes/), most plants in the ancestral environment barely contained enough sugars to reach the sweetness detection threshold. [This review](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5003684/) goes into the rabbithole of the real reasons we like sugar, but I notice I’m still confused.

Anyway, the consensus seems to be that sweetness drives us to eat the good plants, while bitterness keeps us away from the bad ones. Accordingly, [a lot of obligatory carnivores](https://doi.org/10.1073%2Fpnas.1118360109) (including your [cat](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1183522/)) have a non-functional sweet receptor, making them indifferent to plants and fruits. Insectivores like armadillos and hedgehogs [don’t appear to like sugar](https://doi.org/10.1016/s0149-7634(05)80213-1) so much either.

In that picture, I would expect sweet receptors to be rather specific. For instance, in mammals, we know only one kind of receptor, a dimer of the [T1R2 and T1R3](https://doi.org/10.1016/S0092-8674(01)00451-2) proteins.[^ifun87qv7lg] Meanwhile, we have dozens of different bitterness receptors (that academics helpfully compiled in the [BitterDB database](https://bitterdb.agri.huji.ac.il/dbbitter.php)). I suppose this reflects the fact that sweetness makes you attracted to a narrow range of chemicals (sugars), while bitterness keeps you away from a wide range of disgusting toxic stuff.

So it’s not surprising that some of our best commercial low-calorie sweeteners don’t look like anything that occurs in nature. If low-calorie sweeteners were common in nature, our taste buds would probably have mutated to become insensitive to them.

There is one documented case of this happening: an African plant, *Pentadiplandra brazzeana*, contains a peptide called [brazzein](https://en.wikipedia.org/wiki/Brazzein) that is 1,500 times sweeter than sucrose. Presumably, this is to trick the local gorillas into eating the fruits and pooping the seeds into exciting new territories, without spending too much energy on sugars. But [a genetic analysis](https://doi.org/10.1002/ajpa.23046) found that western gorillas have a few mutations in their taste receptors that prevent brazzein from binding, and now the apes eat all kinds of fruits but never *P. brazzeana*.

(Nice story idea for a children’s book: One day, everybody in Gorilla Village ate the delicious New Fruit, except the village’s weirdo grumpy gorilla. Then everybody starved to death, and only the mutant was left to repopulate the world. The moral of the story? “Have superior genetics or die.”)

(There are a few [other](https://en.wikipedia.org/wiki/Monellin) [naturally](https://en.wikipedia.org/wiki/Neohesperidin_dihydrochalcone)-[occurring](https://en.wikipedia.org/wiki/Mabinlin) [low-calorie](https://en.wikipedia.org/wiki/Mogroside) [sweeteners](https://en.wikipedia.org/wiki/Steviol_glycoside), but there are uncommon and it’s not clear why they exist. My favourite is [thaumatin](https://en.wikipedia.org/wiki/Thaumatin), a protein involved in the immune system of a plant, who just happens to be 100,000 times more potent than sucrose. As far as I can tell, [nobody knows why](https://link.springer.com/article/10.1007/s00299-010-0826-8).)

Altogether, this illustrates the fact that it’s not common for our sweet receptors to get activated by small calorieless molecules, and chemists must have eaten a lot of weird things to find the synthetic sweeteners we currently use.

This is when things get out of control.

The big pharma tasting machinery
================================

Hear me out: there are [about 4000 clinical trials](https://www.statista.com/statistics/1249010/clinical-trials-started-by-trial-phase-worldwide/) worldwide each year. Tasting is [an important part of drug development](https://database.ich.org/sites/default/files/E11_R1_Addendum.pdf) – if anything, it may determine how the pill should be coated or whether to use a capsule. Therefore, *several thousands* of new compounds must be tasted by clinical trial participants *every year*.

Why didn’t we discover any new artificial sweetener this way? What are the chances that the top 5 most used synthetic sweeteners all come from chemists accidentally ingesting their works in progress, and *not a single one* from the cohorts of people tasting thousands of molecules all the time in controlled settings?

Let’s do a back-of-the-envelope calculation.

There are [more than 19,000](https://www.fda.gov/media/115824/download) FDA-approved prescription drugs on the market, 40% of which are [administered orally](https://doi.org/10.1016/j.chembiol.2014.08.013),

About [half of Phase III clinical trials fail](https://pubmed.ncbi.nlm.nih.gov/27723879/), and this is due to a lack of efficacy 60% of the time.

So, we can estimate that the number of inactive/non-toxic oral drugs that were tasted by people in Phase III trials is upwards of 4,000.

How many were sweet? I looked at clinical trials search engines and wasn’t able to find any report of a strong sweet taste (the only hit was dextroamphetamine-saccharate, which basically contains sucrose). And of course, *zero* of these 4,000 chemicals ended up being commercialized as artificial sweeteners.

Meanwhile, rule-breaking chemists accidentally found the five commercial molecules mentioned above. Therefore, chemists must have tasted *at least* 20,000 molecules to find all five of them, and that’s only counting the ones which were actually commercialized. That’s pretty impressive.

I hear your objections
======================

**What if pharma companies are scared to use a potential medicine as a culinary additive?**  
The estimate above only counts drugs that were found to be ineffective, but maybe they still had *some* activity, at least theoretical, and that doesn’t sound safe. However, it happened in the past that a drug developed for something ended up [repurposed](https://en.wikipedia.org/wiki/Drug_repositioning) for something else entirely. A famous case is minoxidil, which was developed to treat ulcers, but ended up being used [to prevent hair loss](https://en.wikipedia.org/wiki/Minoxidil#History). So that doesn’t seem to be a huge barrier.

**What if people have already fully optimized sweeteners and there’s no market for new ones?**  
Our current sweeteners are not bad – at least we’re not using [straight-up motherfucking lead](https://en.wikipedia.org/wiki/Lead(II)_acetate#Sweetener) like in Ancient Rome – but they are not perfect either. First, all the sweeteners I know taste bad. Second, aspartame is (lightly) suspected to cause cancer. Third, people *are* looking for new sweeteners: there’s no lack of studies using [*in-silico* screening](https://doi.org/10.1016/j.foodchem.2020.128538) or [machine learning](https://doi.org/10.3389/fchem.2019.00035) to find them.

**What if participants don’t report it when they find a drug is delicious?**  
Clinical trials are usually *very* thorough when it comes to reporting side effects – remember the guy in the Moderna vaccine trial who was struck by lightning and [they had to report it as a Serious Adverse Effect](https://metro.co.uk/2020/12/18/covid-vaccine-volunteer-struck-by-lightning-after-moderna-injection-13774498/)? But, fine, maybe people don’t report something as benign as a sweet taste.

In that case, here is something they cannot hide: *a psychedelic trip*.

High probability
================

Like aspartame, [LSD was discovered by a chemist who ingested it by accident](https://en.wikipedia.org/wiki/History_of_lysergic_acid_diethylamide). LSD binds to serotonin receptors, which are also the target of highly-lucrative classes of antidepressants, anti-emetics, and anti-migraine medication. So you can imagine the massive number of serotonin analogues that the pharma industry has fed to clinical trial participants. But, unless they’re hiding things from us, none of these trials resulted in participants tripping balls. From this, I conclude that LSD-level psychedelic molecules must be exceedingly rare.

Just to be sure, I checked the [FDA’s side-effect database](https://open.fda.gov/data/faers/) – it doesn’t have a “walls are breathing” search term, but it has “visual hallucinations”. Most of the results are boring psychiatric drugs like zolpidem or bupropion, with limited recreative potential. I mean, yes, there is [a case report](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3660935/) of a 5-years-old seeing helicopters in her room after taking antibiotics, but I don’t think this has much street value.

Meanwhile, the Psychonaut Wiki lists [about a gazillion psychedelic compounds](https://psychonautwiki.org/w/index.php?title=Lysergamides&_=) with cool names like LSM-775 (they even have one that smells like [Pokémon cards](https://psychonautwiki.org/wiki/MXiPr) – a drug taken only by the *really cool* kids). This is the result of extensive systematic testing by the stoner research community, most notably [the Shulgin family](https://en.wikipedia.org/wiki/Alexander_Shulgin).

Here’s the thing: among the many close analogues of LSD, most are less potent than the original LSD. Did Albert Hofmann hit the most powerful LSD variant on the first try, just by chance? More likely, chemists must also have exhausted a substantial part of all possible molecules in the configuration space around LSD. Generations of chemists must have routinely ingested all kinds of mild psychedelics, felt *mildly* in communion with the Universe, had a *mild* encounter with God, and went on with their research without telling anyone. LSD was just the only one strong enough to be noticed.

If you add the history of LSD to the history of artificial sweeteners, it follows that chemistry researchers are constantly tasting everything they touch, and I will believe that until someone gives me a better explanation. If you are a chemist, explain yourself.

[^oe6rv0gafjc]: There are a few instances of synthetic sweeteners discovered by researchers who were actually looking for synthetic sweeteners, like alitame or neotame, but these were follow-ups to aspartame. 

[^ifun87qv7lg]: Needless to say, the sweetness receptor was discovered by the team of Pr Zuker. I told you, this keeps happening.