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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
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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)
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Regulatory Focus
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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
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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.