Aspirin: The Thousand-Year Secret Behind a Small Pill

Hi everyone, welcome to this episode of Cold-Knowledge Blind Box. Sometimes I really feel my age. Lately I've been taking my elders to the hospital quite a lot. One common anti-inflammatory drug caught my interest: aspirin. Mostly because there's a song called "Aspirin," too. So I got curious and looked up its history. Once I started, I couldn't stop, and that's how this episode came about. Just kidding, but digging into it, I found out that behind this little pill there is a thousand-year-old secret.

Aspirin is generally used to reduce inflammation, but its original ingredient is something very familiar from skincare: salicylic acid. And this

Have you ever thought about it? Suppose you were stranded on a desert island and, to survive, you were only allowed to bring one medicine. What would you pick? If you can't decide, I'd suggest aspirin, which is considered one of the three great "miracle drugs" of the 20th century. Although countless drugs have replaced it as medicine has advanced and new versions have come along, aspirin is still consumed at a rate of 40,000 tons a year today.

Why do humans depend so heavily on one drug, and why does such an important medicine come from one of the most common trees, the willow? How did people peel back the layers and find it? We modern people have advanced medical technology. When we have a fever or our bodies ache, we know we need to take medicine. But what did our ancestors do? In the primitive period, before civilization was born, our early human ancestors, along with their relatives the Neanderthals, instinctively reached for the plants around them and chewed on them whenever their bodies were racked by pain.

Along the way, early humans gradually discovered that some trees and grasses could ease physical pain. But they also found that many plants would poison you if you ate them. At that time, humans left no records, so we don't know exactly which plants our ancestors tried.

Moving forward to around 5000 BC, in the Sumerian city-state known as the Kingdom of Ur, archaeologists unearthed a clay tablet recording the medicine of the Sumerians at that time. Apart from some incantations and the names of demons and monsters, the tablet also listed the names of many natural remedies, such as turtle shell, snake skin and figs. And most importantly, willow was among them. But the tablet did not explain what willow was actually used for. All we know is that if you felt unwell, you might want to try chewing willow bark.

It wasn't until an American came along that people finally figured out how the ancients used willow. Edwin Smith was born in Connecticut, USA, in 1822. His greatest hobby was studying Egyptian history, and he spent a long time studying Egyptian texts.

On January 20, 1862, Smith paid 12 pounds to an antiquities dealer in Egypt for two worn-out herbal papyri. One of them was called the Ebers Papyrus, which recorded the medicinal value of various plants as studied by the ancient Egyptians. The book was written around 3000 BC, and it is said to have been a grave good buried with a mummy. So people at the time believed the mummy must have been a doctor in ancient Egypt. Already in the Egyptian period, the key information that willow could relieve pain was recorded. The wisdom of the ancients was far beyond what we imagine.

By the time of ancient Greece and Rome, people had begun making medicines from willow leaves, mainly to treat swelling, heat and pain. The Roman Empire later split into East and West. The Western Roman Empire fell in 476 AD, while the Eastern Roman Empire, also known as the Byzantine Empire, lasted for another thousand years. But this period is known as the Dark Ages. People's main focus was on religion, so many good things from ancient Greece and Rome were lost, and medicine made little progress.

In the 18th century, a clergyman named Edward Stone began to study the medicinal value of willow bark. Why did he suddenly become interested in willow bark? Because medicine at that time had a concept called the "doctrine of signatures." It held that if people fell ill with a certain disease, the cause of the disease and the medicine to cure it should be found in the same place.

It sounds quite imaginative, and it was. Put simply, Reverend Stone noticed that stagnant ditches could make people run fevers and shiver with chills. We know today that this was malaria, but people back then didn't know it was caused by mosquitoes. They only knew that dirty ditches made people sick. According to the doctrine of signatures, if someone got sick beside a ditch, then the cure should also be beside that ditch.

So Reverend Stone had a bright idea: why not try the willow bark that grows by the water? He collected some willow bark and started experimenting. He found a group of relatives and friends, and gave the patients powder ground from willow bark, once every four hours. The result was that willow bark had a remarkable effect in bringing down their fevers.

Reverend Stone made the results public. But we now know that his belief that willow was effective against malaria, a type of intermittent fever, was mistaken. Willow bark brought down fevers only by treating the symptoms, not the root cause. The malaria parasite was not actually killed.

Still, Reverend Stone brought willow bark back into public view, and this had an important influence on the birth of aspirin.

By the 19th century, European industry had advanced enormously, and there were major breakthroughs in chemistry. Before, people only knew which plants could cure diseases. But now scientists wanted to take one step further. They wanted to figure out which substance inside those plants was actually doing the work.

This effort, however, ended up as a disaster. The first thing scientists managed to purify in their laboratories was opium. Although it can relieve pain in medicine, it is extremely addictive. Pharmacists in France and Germany purified morphine in their labs, and willow was not given priority.

It wasn't until 1828 that Johann Buchner, a pharmacist at the University of Munich, extracted a bitter, yellow crystal from willow bark and gave it a name: salicin. In 1838, the Italian Raffaele Piria extracted a strong acid from salicin and named it salicylic acid. So after thousands of years of back and forth, it turned out that this was the stuff in willow bark that relieved pain.

But salicylic acid was still a crucial step away from aspirin, and this is the most interesting step in pharmaceutical science. As the name suggests, salicylic acid is an acid, and acids can do a lot of damage to the body. So people soon found that this substance had too many side effects, causing serious gastrointestinal reactions.

Even today, aspirin's side effects are clearly listed as stomach discomfort, and even stomach ulcers and gastrointestinal bleeding. The birth of a drug usually involves patching things up. You add something to an existing substance, or take something away, so that the effect is kept while side effects are reduced. This is a stage that nearly every drug has to go through.

Whoever managed to turn salicylic acid into aspirin would almost certainly have won a Nobel Prize. But aspirin's birth did not earn a Nobel Prize, for a simple reason: nobody could say for sure who had really done the job.

In the 19th century, Germany rose rapidly under the leadership of "Iron Chancellor" Otto von Bismarck. Germany's industry rose along with the country, and chemistry was the most important discipline in industry. So in the second half of the 19th century, almost every first-rate European chemist had some connection with Germany, either by studying there or working there.

As Germany rose, a giant pharmaceutical company was born: Bayer. Bayer began as a company that dealt in dyes. But because dyes involve chemistry, it had a huge advantage when it turned to chemical drugs.

In 1890, Bayer set up a dedicated pharmaceutical department, and this is where aspirin was born. In 1894, a young man named Felix Hoffmann joined Bayer after an interview.

His father had suffered from severe rheumatism for many years and was in great pain. We know that salicylic acid itself can relieve pain. As early as 1876, the medical journal The Lancet had published that salicylate could relieve fever and pain in rheumatism patients. So Hoffmann's father began taking sodium salicylate.

But this substance caused serious damage to his old father's stomach. So Hoffmann set out to improve salicylic acid. Since it was an acid, he thought, could he add something to shield the acid? That led him to acetylation: salicylic acid became acetylsalicylic acid, and acetylsalicylic acid is none other than the famous aspirin.

It was not only effective, but its toxicity was greatly reduced. But the dramatic part is that Hoffmann was not only working on acetylsalicylic acid. He was also trying to acetylate other substances. He thought acetylation was practically invincible and could be applied to other materials.

He thought of morphine. Morphine relieved pain very well, but its major drawback was severe addiction. What if acetylating morphine could produce a drug that relieved pain without causing addiction?

Hoffmann had high hopes, and he finally synthesized diacetylmorphine. Yes, this is another famous name: heroin.

So in just two weeks, Hoffmann brought the world both one of its most useful drugs and one of its most harmful narcotics.

Do you know why it's called heroin? Because at the time they recruited a few volunteers to try the drug, and after taking it, the volunteers instantly felt like heroes, filled with a spirit that could move mountains. So the drug's brand name was linked to the word "hero": Hero, heroine, heroin.

As for the poor but truly valuable drug, acetylsalicylic acid, Bayer didn't start paying real attention to it until 1899. They gave it a catchy name, Aspirin, but people still did not truly take notice of it.

What really made the whole world accept aspirin was the 1918 Spanish flu.

At that time, a quarter of the world's population was infected, about 500 million people, and between 20 and 50 million died. It was the deadliest epidemic after the Black Death.

The plague started at the end of World War I. It was caused by the H1N1 influenza virus. Unlike our recent COVID-19, the Spanish flu killed young people at the highest rate. People aged 20 to 35 had very strong immune systems. When their bodies were infected by the virus, their immune responses were extremely powerful, and what killed them was precisely this excessive self-immune reaction. Patients developed symptoms such as difficulty breathing, high fever, headaches and coughing up blood.

And at that time there was no modern medical technology that could sequence a virus and then produce a vaccine. So the plague was almost unbeatable. What could our small aspirin do?

As we've said all along, aspirin is really a drug that treats the symptoms rather than the cause. It can bring down fever and relieve pain. It can't kill a virus, but it can ease the symptoms of infection. This made people realize that perhaps only this small aspirin could buy them time to survive.

Two years later, the virus was gone, and aspirin, without any dispute, entered its own era.

A hundred years on, people still use it, and its role in treating cardiovascular disease has gradually been recognized. Aspirin has even been found to significantly reduce the risk of colorectal cancer and the risk of death from it.

Up to this point, it might seem that the Nobel Prize should have gone to Hoffmann, who successfully acetylated salicylic acid. But stories are just stories. Hoffmann treated his father's rheumatism, and it was on that basis that he developed aspirin. Bayer's claim was simply a publicity stunt.

In fact, the reason the Nobel Prize never went to Hoffmann is this: on the 50th anniversary of aspirin's birth, a man named Arthur Eichengrün published an article. He had been Hoffmann's superior back then. The task of synthesizing acetylated salicylic acid had been assigned to Hoffmann by Eichengrün himself. Hoffmann didn't even know what the purpose of the task was. He was only completing the work his superior had given him. And the synthesis method had been told to Hoffmann by Eichengrün.

About two weeks after publishing this article, the 82-year-old gentleman passed away. It seemed his wish had been fulfilled.

People then began to dig into this dark chapter of history. It turned out that Eichengrün was Jewish. During World War II he was even sent to a concentration camp. He survived through these terrible hardships, and it wasn't until 50 years later that he told the world the truth.

In 1971, someone finally won the Nobel Prize for aspirin. The prize was awarded for explaining how aspirin works: it inhibits the production of prostaglandins and thromboxanes. I think this was the scientific community's way of giving aspirin its due.

Finally, one last note: if you are ill, always see a doctor at a proper hospital. That's it for Cold-Knowledge Blind Box. See you next time.

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