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Perspective Serendipity and Drug Discoveries By Max Sherman T he words luck and serendipity are frequently used interchangeably to describe the evolution of many scientific discoveries. There are nuances of difference, however. Luck is an English word derived from the Middle High German gelűcke, which means both happiness and good fortune—conditions that are not necessarily identical.1 The word serendipity was coined by Horace Walpole in 1754; it describes discoveries made by accident and sagacity. Sagacity, defined as penetrating intelligence, keen perception and sound judgment, is essential for serendipity. Walpole used serendipity to describe some of his own accidental discoveries, but it did not appear in major dictionaries until 1974.2 Since then, serendipity has been used with increasing frequency, and luck much less often, to describe medical breakthroughs and drug discoveries. Good fortune, however, is more apt to occur when a well-trained scientist or clinician is unbounded by traditional theory and uses his or her intuition, imagination and creativity. This article describes a few serendipitous drug discoveries and discusses whether the good fortune will continue. Penicillin The drug most closely associated with serendipity is penicillin. Most of us in the regulatory profession are acquainted with that discovery and know we owe our antibiotic armamentarium to a dirty Petri dish in Alexander Fleming’s laboratory. Fleming was an English physician and microbiologist. Perhaps not all know that the organism, the weather, a German refugee chemist and a rotten melon also played a major role.3 Development began in 1929, when Fleming noticed a zone of inhibition around a colony of penicillium mold on an agar plate of Staphlycoccus. The mold that contaminated the culture was a very rare organism traced to a mycology laboratory one floor below. Its spore wafted up the stairway to settle on one of Fleming’s dishes at a particularly critical instant—precisely when he implanted the agar with the bacteria. There had been an intense heat wave in London that broke the day Fleming 46 December 2008 opened the dish, and the cooler weather allowed the penicillium spore to survive. The story almost ended there, for Fleming could not siphon off the fluid produced by the mold and inject it into patients. It was not until eight years later that Ernst Boris Chain, a German expatriate chemist, developed a method for producing a stable powder form. The first clinical trial was performed on an infected patient who improved dramatically with each injection. Unfortunately, the drug supply ran out and the patient died, but his initial response encouraged further production and testing in five patients, four of whom had miraculous recoveries. Large-scale production followed in the US and a search for a more productive strain of the penicillium mold was sought. After worldwide exploration, an improved strain was found on a rotting cantaloupe in Peoria, Illinois by a laboratory aide. (The fermentation plant used to manufacture penicillin was located in Peoria.) The organism proved to be Penicillium chrysogenum, a strain that produced 3,000 times more penicillin than Fleming’s original mold. Not long after, the first 40 mg isolated by Chain in 1937 had increased to four tons of pure drug produced in 1945. Insulin Fred Banting and J.J.R. Macleod won the Nobel Prize in 1923 for the discovery of insulin. Their discovery was monumental, but it would not have been possible without work done at the University of Strasbourg in 1889. Oskar Minkowski and Joseph von Mering had disagreed on whether pancreatic enzymes were needed to digest fat. They decided to remove the pancreas from a dog and observe the results. Some years later, Minkowski described how he kept the depancreatized dog tied up in the lab while waiting for von Mering to return from a trip. Even though the animal was housebroken and taken out regularly, it kept urinating on the floor. Minkowski decided to test the urine for the presence of sugar. His tests revealed 12% sugar in the dog’s urine and that the dog was suffering from something indistinguishable from diabetes mellitus. Thus, for the first time, experimental diabetes was produced and the earliest glimpse was given into the possible cause of that disease.4 The more common story was that Minkowski’s attention to the urine was due to flies attracted to the sugar. Minkowski, however, denied this version.5 His denial is not surprising, as it is unsettling for scientists to admit that their discoveries have occurred purely by accident. Psychotropic Drugs Major classes of psychotropic drugs including lithium, chlorpromazine, imipramine, reserpine and chlordiazepoxide were serendipitously discovered in the 1950s and 1960s. Lithium was discovered in research on urine samples from manic patients. Urea was found to be more abundant in their urine than in normal patients and more toxic when injected into guinea pigs. The researcher postulated that the toxicity might be due to the presence of uric acid. He carried out a number of tests to determine the urea’s toxicity using varying concentrations of uric acid. Because uric acid is highly insoluble, its most soluble salt—lithium urate—was used in his experiments. The salt was found to produce a calming action on guinea pigs, an effect not due to the urate component but to the presence of lithium ions.6 Chlorpromazine was originally designed to be used for its antihistamine effects and found to be effective in treating schizophrenia. Imipramine, a chemically similar drug, was found to be surprisingly inactive against schizophrenia, but effective for its antidepressant effects. Reserpine had been designed to treat high blood pressure when it was found to be useful in treating psychiatric patients.6 Chlordiazepoxide was surprisingly effective as a tranquillizing drug, even though similar compounds had no such properties. During its synthesis, chlordiazepoxide underwent an unexpected intra-molecular arrangement.2 was the first cancer chemotherapy agent approved by the US Food and Drug Administration. Aspirin, used for more than 100 years for pain and fever, is now recommended for preventing heart attacks. Lidocaine, a local anesthetic, is now used to treat cardiac arrhythmias. Minoxidil, used topically to grow hair, was originally, and is still used for hypertension.2 Iproniazid, an early antidepressant, was initially employed to cure tuberculosis. The drug’s antidepressant effects were discovered in a chronic tuberculosis ward where patients who took the drug become euphoric.6 Sildenafil (Viagra) was a compound developed to treat angina. Thalidomide, a teratogen, was originally designed as a sedative; now it is a mainstay for patients with multiple myeloma and used to treat certain forms of leprosy.8 Bupropion, an antidepressant, was inadvertently found to lessen the effects of nicotine. Eflornithine (Vaniqa) was useful in treating African sleeping sickness. It was later discovered to suppress the enzyme that causes facial hair to grow.6 Future Implications for Drug Discovery Research today is targeted toward a specific goal Existing Drugs With New Uses Many other drugs have been accidentally found to benefit a new indication.6 The list includes dimenhydrinate, mechlorethamine, aspirin, lidocaine, minoxidil, iproniazid, sildenafil, thalidomide, bupropion and eflornithine. Dimenhydrinate, an antihistamine, became one of the drugs of choice for motion sickness.7 Mechlorethamine was used as a poisonous gas during World War I. Because of its destructive effect on white blood cells it was found useful in treating Hodgkin’s disease and other lymphomas. Mustargen (the trade name) PassAlong_Ad_1207.indd 1 10/26/07 2:30:15 PM Regulatory Focus 47 and new drug discoveries are the result of intense planning, interminable research, long-term clinical studies, laborious and comprehensive data collection and statistical analysis. There is almost no room for significant variation. In light of the expenses involved and tight schedules, scientists have little time to pursue new ideas. Even if they did, our educational system no longer fosters the skills needed for creativity. According to one author, current curricula completely ignore the process of how discoveries and current concepts came to be accepted.6 There is now little attempt to teach, or even encourage the kind of creativity and complex synthesizing of ideas that once enabled discoverers to perform major breakthroughs. Drastic changes in medical practice and academic medicine in the past 30 years have led to severe constriction of a clinician’s treatment time per patient and any opportunity for serendipitous discovery. Hospital stays are shorter, preventing longitudinal studies with inpatients who are now regularly discharged before the effects of a new therapeutic regimen becomes clear.9 In psychiatric practice, for example, insurance company requirements for time limits and paperwork lead to clinical practices with little time for fresh observations and much less 48 December 2008 discovery.9 Considering all of these factors, it would appear that serendipitous discoveries are less likely to occur in the future. References 1. Rescher N. Luck—the Brilliant Randomness of Everyday Life. Farrar, Straus, Giroux, New York, 1995. 2. Roberts RM. Serendipity—Accidental Discoveries in Science. John Wiley & Sons, New York, 1989. 3. Bud R. Penicillin: Triumph and Tragedy. Oxford University Press, London, 2006. 4. Cannon WC. The Way of an Investigator. Norton & Company, New York, 1945. 5. Bliss M. The Discovery of Insulin. University of Chicago Press, Chicago, 1982. 6. Meyers MA. Happy Accidents—Serendipity in Modern Medical Breakthroughs. Arcade Publishing, New York, 2007. 7. Gay LN and Carliner PE. “The prevention and treatment of motion sickness.” Johns Hopkins Medical Bulletin, 1949; 84:470-87. 8. Stirling D et al. “Thalidomide—a surprising recovery.” Journal of the American Pharmaceutical Association, 1997;Vol NS37(3):307-313. 9. Klein DF. “The loss of serendipity in psychopharmacology.” JAMA, 2008; 299(9):1063-65. Author Max Sherman is president of Sherman Consulting Services Inc., in Warsaw, IN. He can be reached via email at maxsherman@ kconline.com.