The discovery of aspirin is a fascinating story (to me, at least). In 1853, the French chemist Charles Frederic Gerhardt (yes, I’m sure he was French) studied a group of organic chemicals called anhydrides (an=without, hydride=water). Among many molecules of this group, he synthesized one called acetylsalicylic acid, or ASA. He then put the vial containing the white powder on a shelf and forgot about it. And there it sat for over 40 years until 1897, when a German chemist named Felix Hoffmann, working for Bayer, the German chemical and pharmaceutical company, rediscovered the compound using a different synthetic procedure, tested it for analgesia, and voila! It was used as an analgesic and antipyretic (fever-lowering) since then.
But the story doesn’t end there. Nobody knew how aspirin worked. It was only in 1971 that it was discovered that aspirin works by inhibiting the enzyme cyclooxygenase (COX). For that discovery, John Robert Vane, working for the Royal College of Surgeons (no, he was not a surgeon; he was a real scientist), received the Nobel Prize. What’s the big deal about this enzyme? It is a critical enzyme in the synthesis of a group of substances called prostaglandins, which are mediators of inflammation and pain. So aspirin very quickly became the mainstay of treatment for arthritis and other inflammatory diseases. In its soluble form, sodium salicylate, it was used in the treatment of Crohn’s disease, or colitis, a devastating inflammatory disease of the colon. And within a few short years, a new group of COX inhibitors, called NSAIDs (non-steroidal anti-inflammatory drugs), was synthesized. Famous members of this group are ibuprofen (Advil), naproxen (Naprosyn), and others.
But wait, wait, there is more. In the late 70s, it was discovered that low dose aspirin or NSAID inhibit platelet aggregation, which was the basis for using them as a preventative for myocardial infarction.
This is quite a remarkable demonstration how learning the molecular details of biology and pharmacology can lead in totally unexpected directions, and to undreamed of new therapies.
New respect for the humble DEET
Who doesn’t know DEET? Certainly, nobody who has ever gone on a hiking or camping trip. I personally experienced the wrath of a cloud of mosquitoes when I forgot “to DEET”. We were on our way to watch the chimps in Africa, and my memory of that particular outing is total body itch. If there are species that I wouldn’t shed tears if they became extinct, it is the mosquitoes.
Like aspirin, DEET was synthesized a long time ago (over 50 years ago), and notwithstanding the long-held reasonable assumption that it is a mosquito repellent, nobody really investigated its mode of action. That is surprising, given the medical importance of mosquito-borne diseases, such as malaria, dengue fever, yellow fever, and more.
In a story in Science magazine, a group of molecular neurobiologists from Rockefeller University published a report on DEET’s mode action. And surprise, surprise: It is not a repellent. It doesn’t smell bad to the mosquito. In fact, it doesn’t smell at all.
Female mosquitoes (and fruit flies) smell lactic acid in our sweat and carbon dioxide and a certain alcohol (1-octen-3-ol) in our breath. Those three odorants evoke in the little pests the equivalent of a Pavlovian response—but instead of drooling, they home in like heat-seeking missiles.
How do they smell it? For each of the 3 odorants, there is a specific receptor on the mosquito’s antennas. Once a molecule of, say, lactic acid lands on its receptor, it triggers an electrical discharge in the olfactory nerve leading to the brain. And there, a behavioral pattern is unleashed that sends the bloodsucker hurtling toward the source of the odor.
DEET works by occupying the receptors so that the odorants cannot bind. Result: The insect is unaware of them, no chemical attraction, no bite.
Could the aspirin story be repeated?
I think so. DEET was discovered the old fashioned way; chemists synthesized thousands of compounds which were then tested for any activity imaginable. This approach gave us most of the drugs being used to date. But it also has a weakness. Because the drug was discovered by the hit or miss approach and not by designing it to bind to a specific target, its binding to the target molecule was essentially accidental and almost never was at a maximum. It was good enough and was rushed to market. Now that we know the molecular details of the mode of action of DEET, chemists can synthesize new classes of molecules that will bind more specifically and more tightly to the receptors. In other words, they can create less toxic and vastly more effective compounds that will protect us from insect bites. This is important because DEET is toxic to infants. But even more important, blood-feeding insects transmit many of the world’s deadliest diseases. Malaria alone infects an estimated 500 million people annually, leading to the deaths of about 1 million people per year! These are mind-boggling numbers. Spraying or dabbing on a new and improved version of DEET, could turn out to be a powerful means of malaria control. Bill and Melinda, are you listening?
Let’s not forget the repulsive ticks; they are attracted to humans by exactly the same odorants. Lyme disease, tick-borne relapsing fever, Rocky Mountain spotted fever, tick typhus—these are all diseases transmitted by ticks. In the new world of global warming, insect-borne diseases are going to become significant public health problems; Ebola and chikungunya are harbingers of what’s coming.
And who knows what else is waiting around the corner once DEET-like drugs are made? After all, did Hoffmann, toiling in the Bayer laboratory, ever dream of what aspirin would turn out to be?