ON AUGUST 10th 1897, Felix Hoffmann, a chemist in the employ of a German dyestuffs company called Bayer, managed to acetylate the phenol group of a compound called salicylic acid. Not, on the face of it, the stuff for which front pages are held. But acetylsalicylic acid has two claims to fame. First, as the world's first truly synthetic drug (ie, not merely an artificial copy of a naturally occurring compound), it paved the way for the modern pharmaceuticals industry. Second, it is probably the most successful medicine in history. For acetylsalicylic acid is better known as aspirin.

Since Hoffmann's synthesis, aspirin has gone from strength to strength. It has not suffered proscription, as happened to its near contemporary, heroin. Nor has it been overtaken by more modern substances. Paracetamol and ibuprofen may have nibbled at its share of the over-the-counter (OTC) painkiller market, but aspirin still outsells them both — in Germany, for instance, half of the OTC market belongs to aspirin-based products. Moreover, as time passes, aspirin looks more and more useful. It was first marketed mainly as an anti-inflammatory, particularly for people suffering from rheumatism, but its popularity as a general-purpose painkiller followed quickly. Lately it has come to be seen as a life-saver — prescribed to those at risk of heart attacks and strokes as a way of preventing the blood clots that cause them. And the future may be even more thrilling, for current research is lining aspirin up to treat one of the nastier types of cancer.

Barking up the right tree

All this springs ultimately from a substance that accumulates in willow trees. Rheumatism has plagued the human race at least since the flowering of the great river cultures of the Middle East. Clay tablets from the Sumerian period describe the use of willow leaves to treat it. The Egyptians were also aware of the pain-relieving effects of potions made from myrtle or willow leaves.

Extracts from the bark and leaves of the willow, myrtle and a number of other plants rely for their effect on the presence of salicylic acid, an organic compound composed of seven carbon atoms, six hydrogens and three oxygens. Edward Stone, a vicar from Chipping Norton in Oxfordshire, is generally recognised as the man who gave the first scientific description of the effects of willow bark. In 1763 he wrote a letter to the Earl of Macclesfield, then president of the Royal Society in London, in which he describes treating patients suffering from ague (fever) with 20 grains (approximately a gram) of powdered willow bark in a dram of water every four hours.

Stone's interest in willows was due to the ancient "Doctrine of Signatures" — whereby the cause of a disease offers a clue to its treatment. According to Stone:
As this tree delights in a moist or wet soil, where agues chiefly abound, the general maxim that many natural maladies carry their cures along with them or that their remedies lie not far from their causes was so very apposite to this particular case that I could not help applying it; and that this might be the intention of Providence here, I must own, had some little weight with me.

In 1829 the action moved to France. Henri Leroux, a pharmacist, obtained a compound of salicylic acid, known as salicin, in crystalline form for the first time, and Raffaele Piria, an Italian chemist, then succeeded in splitting it up to obtain the acid in its pure state. Reports of its beneficial properties spread quickly and demand grew. Hermann Kolbe, professor of chemistry at Marburg University, in north-western Germany, discovered the compound's chemical structure and succeeded in making it artificially in 1859. This allowed salicylic acid to be produced on an industrial scale, and by 1874 a factory in Dresden was able to sell it at a tenth of the price of material extracted from willow bark.

However, salicylic acid has unpleasant side-effects. Most notably, it irritates the stomach — and many patients were simply unable to tolerate its unpleasant taste. One such patient was the father of Felix Hoffmann, and it was his father's complaints that stimulated the younger Hoffmann to play around with salicylic acid in order to produce something as effective as a treatment for rheumatism, but more palatable.

The head of Bayer's pharmacology laboratory, Heinrich Dreser, quickly tested Hoffmann's new compound on himself. He then set up a series of animal experiments (another first for aspirin; the testing of drugs on animals had never before been done in an industrial setting) and soon demonstrated the anti-inflammatory and analgesic effects of acetylsalicylic acid on his experimental animals. Tests on people began soon afterwards in the Deaconess Hospital in Halle an der Saale.

Following an enthusiastic report from the medical staff there, Bayer realized that it had a major discovery on its hands. In yet another first — the first mass marketing of any drug — the company sent information about aspirin to 30,000 doctors. By 1914, aspirin was making a healthy contribution to Bayer's profits. And although many of its foreign rights were confiscated by Germany's enemies after the first world war, Bayer still leads the world in aspirin production, selling 11 billion tablets a year.

Unlike many centenarians, though, aspirin is not ready to retire. In fact, its future seems brighter than ever following a number of clinical trials stimulated by the discovery, in 1971, of how it actually works.

Keep on taking the tablets

In a piece of research for which he was awarded both a Nobel prize and a knighthood, John Vane, who was then employed by the Royal College of Surgeons in London, showed that aspirin suppresses the production of local hormones known as prostoglandins.

These are found in most tissues of the body, and they have a number of different functions including regulating the contraction of the so-called "smooth" muscle that is found in the blood vessels, the stomach, the intestines and the bladder, and mediating pain and inflammation. But they also regulate the aggregation of platelets — scraps of cells in the bloodstream that help to form clots. Suppress the prostoglandins in platelets, therefore, and you suppress the formation of the sort of clots that trigger heart attacks and strokes.

The Physicians' Health Study — organised by Charles Hennekens of Harvard University and published in 1989 — involved more than 22,000 healthy American doctors. It showed that an aspirin a day reduces the incidence of heart attacks by half, and that the drug can also help to prevent thrombosis and strokes.

This was followed up by a so-called "meta-analysis" of clinical trials of aspirin published in 1994 by Richard Peto and Rory Collins of Oxford University. They reviewed the results of 300 published trials of aspirin, involving some 140,000 patients — the largest number of patients ever reviewed at one time. The message was clear: if people under 70 who are at risk of heart disease were to take aspirin regularly, the number of deaths from such disease across the world could be reduced by 100,000 a year. Many people, including a lot of doctors, now begin their day with an aspirin.

That aspirin's uses may not stop there has been suggested by Sam Shapiro and his colleagues at Boston University. About five years ago they developed a hypothesis, based on data from experimental animals, that bowel cancer might be prevented by a regular dose of aspirin. Some 15-20 studies of this idea have since been carried out, and they suggest that it is correct — the reduction being somewhere between 30% and 50%. Aspirin, Dr Shapiro believes, interferes with the biochemical mechanism that causes cells lining the bowel to become cancerous. This mechanism appears to involve prostoglandins in at least two of its stages. Keeping them suppressed keeps the cancer suppressed as well. There is clearly life in the old drug yet.