Tales of the unexpected: Medicine's accidental discoveries

From Botox and viagra to penicillin, some of the greatest breakthrough cures have been discovered by happy serendipity. Roger Dobson reports

The cosmetically desirable effects of Botox were first discovered by surgeons who noticed the softening of patients' frown lines following treatment for eye-muscle disorders When surgeons switched on the power to electrodes in the brain of an obese man to try to reduce his appetite, the results were not those that had been expected. As the electrodes were being moved around the brain to locate the food control areas, the patent began to get memories of events long forgotten. Detailed recollections, including a walk in the park with a girlfriend three decades earlier, and other long-past social occasions with friends, including memories of what they wore and the weather on specific days, flooded back. Entirely by accident, the neurosurgeons had stimulated memory circuits in the brain and stumbled upon a possible treatment for those with memory problems. Now, the team are applying the same approach to patients with Alzheimer's disease as a therapy to boost degenerating memory circuits.

"We were, in effect, turning up the volume of the memory circuits," says Professor Andres Lozano, a neurosurgeon at Toronto Western Hospital. "It opens a window into what areas of the brain are involved in laying down and retrieving memories. For me, it was really a eureka moment.'' It was also another example of serendipity in medicine. Medicine is littered with such accidental discoveries, including those for penicillin, vaccinations, X-rays, anaesthesia and Viagra. Many antibiotics and the bacterial cause of stomach ulcers, as well as the idea of chemotherapy drugs, were also discovered by chance. In some cases, the discoveries were put down to luck, while, in others, scientists found one effect while looking for, and expecting, something completely different. Professor Thomas Ban, a psychiatrist and author of a report on the role of serendipity in drug discovery, says that while luck can be involved, other factors are necessary, too. "Pasteur said that chance favours the prepared mind, and I think he was spot-on,'' he says. "All happy accidents in science have one thing in common: each was recognised, evaluated and acted upon by scientists with open, creative minds. Discovery needs luck, invention, intellect none can do without the others." Potassium bromide The oldest widely used sedative in medicine, its effects were discovered by accident. "The discovery was one of the many quaint examples of serendipity in which an utterly false theory led to correct empirical results,'' says Professor Ban. Charles Lockock, like most physicians of the mid-19th century, believed that there was a cause-effect relationship between masturbation, convulsions and epilepsy. Bromides were known to curb the sex drive, so the London doctor set out to control epilepsy by using bromide to reduce the frequency of masturbation. The treatment was a success in that it helped to control convulsions, but not through the route that Lockock had intended. Viagra The telephone call from a doctor in Merthyr Tydfil was one of the first clues. He had been running a small clinical trial on a new drug that had been designed for treating patients with angina. With other trials showing little efficacy for treating the disease, the future for the compound known as UK-92,480 was looking bleak. When the doctor gave Pfizer the results, he mentioned that there had been some side effects among the healthy volunteers on the trial at Merthyr Tydfil, including indigestion and back pain. And, he added, some of the men had involuntary erections when they took the drug. Scientists quickly discovered the scientific reason for the erections, and five years later and after much research, Pfizer applied for marketing approval for the drug not for angina, this time, but for male impotence. Ten years on, Viagra has been used by more than 30 million men worldwide for impotence, and researchers are still finding

new uses. The drug that nearly didn't make it is currently being used or investigated for treating more than a dozen diseases and health problems. Vaccination When Edward Jenner moved to practise medicine in rural Gloucestershire, he heard of a local saying that if a man wanted a woman who would not be scarred by the deadly smallpox disease, he should marry a milkmaid. This folk tale stemmed from the fact that milkmaids were vulnerable to cowpox, a chronic disease of cows that appeared as a rash on the milkmaids' hands. As a result of this, in 1796 Jenner used cowpox to inoculate an eight-year-old boy called James, then exposed him, some weeks later, to smallpox. The cowpox was found to protect against smallpox. Within six years, vaccination for the disease was an established practice, and it was Jenner's work that led to the eradication of smallpox in 1977, and the widespread use of vaccination. Botulinum Toxin In 1895, three members of a music club in Ellezelles, Belgium died and 34 fell ill, after eating a meal of raw salted ham. The culprit was eventually found to be Clostridium botulinum, which produces botulinum toxin, the most deadly poison of all. Work started in 1920, with researchers trying to isolate the toxin, but it wasn't until the 1950s that they discovered that the toxin could be used in tiny doses to treat "crossed eyes", spasms of the eyelids and excessive underarm sweating. The cosmetically desirable effects of Botox were first discovered by Canadian surgeons Alastair and Jean Carruthers, a husband and wife team who noticed the softening of patients' frown lines following treatment for eye-muscle disorders. "Its present cosmetic and non-cosmetic applications could certainly be considered a journey of serendipity,'' says Dr Arnold Klein of the University of California. Later, Dr Richard Glogau, a dermatologist at the University of California, noticed a curious side effect when he injected Botox into the head and facial muscles of patients. The bacteria was being injected for cosmetic reasons, to temporarily get rid of wrinkles, but Glogau and his team noticed that patients who also had regular migraines were no longer getting them. Further research showed that botulinum toxin A injected into the muscles of the brow, eyes, forehead, side of the head and back of the head near the neck could induce immediate headache relief that may last for up to six months. Penicillin In 1928, after a period away from his laboratory at St Mary's Medical School in London, Alexander Fleming noticed that a mould had infected dishes where he had been growing experimental bacteria. Curiously, the area surrounding the mould growing in the dish was clear, suggesting that the bacteria could not survive near the

mould. Fleming predicted that a compound produced by the mould must have an antibacterial action. He called the new chemical penicillin. Along with the other antibiotics, it revolutionised healthcare, and dramatically reduced mortality rates. He was awarded the Nobel Prize in 1945. Librium and Valium For months, the small box labelled Ro5-0690 had gathered dust. The product of work on synthetic dyes, it had been developed by Leo Sternbach, a pharmacist at Hoffmann-La Roche. During a routine clean-up, and Ro5-0690 was sent off to see if it had any pharmacological activity. The tests showed it to be highly effective. Ro50690 became the first anxiolytic benzodiazepine and was introduced in 1960 with the brand name Librium. Three years later, another anxiolytic benzodiazepine called diazepam (Valium) was introduced. Benzodiazepines revolutionised treatment for schizophrenia, depression and bipolar disorder. "They became one of the most lucrative drugs thanks to luck," said Professor Ban. Antidepressants In 1956, Roland Kuhn, a Swiss psychiatrist, suggested to Geigy that its compound G 22,355 might have a therapeutic effect in schizophrenia. But tests showed it to be ineffective for the conditions. Just before he returned the drugs to the maker, Kuhn gave it to a patient with severe depression. Spurred by the apparent beneficial effect, Kuhn extended his trial. Not only did it have favourable effects, the patients relapsed when the drug was stopped. Within a year, G 22,355 had become the first tricyclic antidepressant, a family of drugs since used by millions. Quinine South American Indians discovered quinine and its anti-malarial powers by accident. The Peruvian natives found that if they drank from water close to cinchona trees, their fever would be eased. It is now known that the bark is a source of quinine, and Jesuit missionaries are recorded as having first used quinine from the tree to fight malaria in Peru in the 17th century. Quinine was brought to Europe in the same century, and the drug was eventually synthesised to become of a successful treatment for the condition, until it was superseded by other antimalarials. Insulin When two German doctors removed the pancreas from a dog, their plan was to study digestion processes. But they noticed that the dog's urine was attracting unusually large number of flies. Tests showed that they were attracted by high levels of sugar in the urine a symptom of diabetes. The existence of diabetes in healthy animals led to an understanding of the pancreas's role in diabetes. It also led to the identification of insulin and treatment of the disease.