Bitter is the coffee

Many of us don’t go through the day without having at least one cup of coffee, and some hardcore enthusiasts I’ve met spend the whole day drinking coffee instead of water, only to finish strong with a 9pm espresso. No later so it won’t affect their sleep.

Our dependence on coffee is partially due to the functional addiction caffeine induces: once it leaves the body, we feel more tired than before, and we crave more. We believe we can’t function without it and see it as our means of coping with constant demands for performance.

To a large extent, however, we drink coffee because we have a lifestyle dependence on it. It fills many gaps in our often boring days and we like it for its taste and flavour, and for its bitterness. This latter liking is acquired, and many drown out the bitter taste with sugar and dairy products. But if you’re a true fan of coffee, you probably want the bitterness and appreciate the additives for the new experience they create.

I was intrigued when I found that in 2016 a US company called Senomyx claimed in patent number US 9.247,759 B2 a way to reduce consistently the perceived bitterness of coffee. The food and pharmaceutical industries have been masking out bitter tastes for a long time. The additives used are trivial – sugar, salt – or already widely used and derived from natural sources: gluconate, carboxymethylcellulose or beta-cyclodextrin. But early in the 2000s companies started looking at ways to block the taste, rather than just mask it. Some potential uses appeared sensible, for example to make very bitter drugs more palatable to patients.

Tasting bitter

We can taste many different compounds as bitter, but can’t tell them apart based on taste, i.e. we can’t discern different kinds of bitter. The intensity of the sensation determines how we react: coffee and tonic water earn our liking, but intensely bitter substances, such as denatonium benzoate, make us so strongly averse that they are used as deterrents to prevent accidental poisoning. Little was known about the molecular basis of our tasting bitter before a team of scientists (Elliot Adler, Mark Hoon, Ken Mueller, Jayaram Chandrashekar, Nicholas Ryba, Charles Szuker, Luxin Feng and Wei Guo) reported in the year 2000 the discovery of a type of taste receptor called T2R (Taste receptor type 2, also abbreviated as TAS2R) responsible for bitter taste detection in mammals.

The biology

Taste receptor cells are found on taste buds covering the surface of the tongue, and in other areas of the mouth. You can see an illustration of a taste bud here. Receptor cells contain structures which allow for interaction with a tastant (a chemical entity eliciting the sensation of taste). Sour and salty are detected by channels in the cell membrane, but sweet, bitter and umami are detected by TRs (type 1 deals with sweet and umami). Adler et al. showed that taste cells contain T2Rs and proved they function as bitter taste receptors. Some only responded to a single compound, like mT2R5 (m for mouse strain) which reacted to cycloheximide, while others were not so selective. Using cell experiments the researchers explained why mice with mutations in T2R5 were about 8 times less sensitive to the repulsive cycloheximide.

Adler’s team showed how a bitter compound can be detected by one or more receptors, and that by blocking those receptors it should be possible to reduce the sensation of bitterness experienced. They also predicted from genome analysis the existence of 40 to 80 different T2Rs in humans.

The chemistry

A study published in 2010 (by Wolfgang Meyerhof, Claudia Batram, Christina Kuhn, Anne Brockhoff, Elke Chudoba, Bernd Bufe, Giovanni Appendino and Maik Behrens) investigated the detection range of human T2Rs (25 known at the time) against a selection of 104 compounds from natural and synthetic sources. A complex picture emerged with most T2Rs detecting multiple compounds – hT2R14 (h for human) was the least selective in this study and responded to 33 compounds – and more than half of the compounds activating up to 3 receptors, with one (diphenidol) found to activate 15 different hT2Rs. This complex detection pattern probably emerged from the evolutionary process which shaped it into a sophisticated means of preventing poisoning. For example, the studies of Meyerhof et al. showed how hT2R46 detected the toxic compound strychnine and the very similar, but about 100-200 times less toxic, brucine. The sensitivity for strychnine over brucine was just about as high as the toxicity factor and orders of magnitude higher than required to detect the poison in food.

It is no surprise that with so many receptors responding to so many different compounds, we end up finding bitter things that are not toxic to us today. Caffeine itself is bitter, but not dangerous in the amount we usually ingest.

Senomyx reported that compound C (below) can be used in taste tests to reduce consistently the perceived bitterness of a coffee fraction (i.e. instant coffee, medium roast or medium-dark roast) to which it had been added. The receptors targeted were hT2R8 and hT2R14, found to respond to bitter compounds in coffee. Compound C was also found to block to different extents the response of 19 other T2Rs, indicating it could be used broadly to reduce the bitterness of products.

Reported synthesis of compound C by Senomyx.

The chemistry for making compound C is nothing to write home about. It’s a simple three step procedure. The sulfonyl chloride starting material is reacted with 4-methoxybenzyl amine to form a sulfonamide, which is then N-alkylated with benzyl bromide under basic conditions. This results in the carboxylic acid being benzylated as well, so the final step involves a base hydrolysis of the benzyl ester to give compound C.

Bitter is the coffee

Animals have developed complicated systems to detect bitter chemicals as a means to avoid poisoning. Although we are now far less reliant on these defense systems, should we try to block them out? I agree there is value in applying this strategy to medical products, especially if intended for children who are more sensitive to bitter taste than adults. But what about foods and drinks?

What got me thinking was the structure of compound C and others Senomyx exemplified. They look to me more like drug molecules than food additives. The compounds chosen would have to be approved by regulatory agencies, so I don’t think there is any real danger there, as far as the science is concerned.

My question regards the principle. Cheating your own senses to avoid disagreeable sensations covers a range from necessity to indulgence. Taking painkillers is a valid improvement to our quality of life made possible by modern science. It is necessary if we are to function normally. Numbing our tongues to eliminate disagreeable taste from a drink we consume for enjoyment is luxury.

Where do we draw the line between necessity and luxury? Is it wrong to make use of any opportunity to increase our satisfaction and make life as enjoyable as possible? No, if it doesn’t contravene legal and moral principles. Is there value in denying ourselves this then? I think the value is in pushing ourselves to pursue more elevated means of satisfaction. Rather than spend time and energy fixing every nuissance, we could be thinking of better ways to find joy in our lives. Or how to acquire a liking for the bitter things.

4 Comments

  1. I really enjoyed this – from the patent history lesson to the philosophical question of whether we should mask or block the bitter.

    Liked by 1 person

    1. danmmercea says:

      The serendipitous discoveries sometimes make for the best stories

      Liked by 1 person

      1. The aspartame discovery story always amused me as well. Licking a random substance off your finger and thinking, hmm, this tastes sweet? Goes against all lab safety guidelines! https://nutrasweet15.weebly.com/history.html

        Like

      2. danmmercea says:

        Tasting chemicals was standard practice. Chemists also cleaned their hands with benzene. We have really come a long way

        Liked by 1 person

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