Serendipity in Modern Medical Breakthroughs

Serendip is the old Arabic name for Ceylon, now known as Sri Lanka.The origin of the word “serendipity” is in a Persian fairy tale,The Three Princes of Serendip, whose traveling heroes were “always making discoveries, by accidents and sagacity, of things they were not in quest of.” In the 16th century, the tale was translated from Persian to Italian, and from Italian to French. Horace Walpole (1717-1797), an English man of letters, encountered it in a collection of oriental tales in French, and coined the English term “serendipity” in a letter to his friend, Horace Mann, dated June 28, 1754.

Today, the word “serendipity” is a word that is used in everyday language.The Oxford English Dictionary defines it as “the faculty of making happy and unexpected discoveries by accident,” and Webster’s New Collegiate Dictionary as “the faculty of finding valuable or agreeable things not sought for.”

According to the Doctor Out of Zebulon column in the Archives of Internal Medicine, “serendipity signifies a mental state in which serenity and stupidity are blended,” as for example, “the serendipity of a cow chewing its cud under a shady tree,” or “the sort of thing that happens to you when on a dull day collecting fossils you find instead a beautiful woman who proves to be neither geologist nor archeologist.” However, this definition is erroneous, at least insofar as scientific discoveries are concerned.No scientific discovery has ever been made by pure luck.All happy accidents in science have one point in common:
“each was recognized, evaluated and acted upon in the light of the discoverer’s total intellectual experience.”
“Chance favors the prepared mind,” as Pasteur (1822- 1896) said, or more precisely: “Dans les champs de l’observation, le hasard ne favorise que les esprits préparés.”Indeed, it is hard to think of a better expression of “serendipity” as one reviews the incredible concatenation of intentional and chance events in medicine’s happy accidents.Salvador Luria, a Nobel
laureate in medicine, deemed it “the chance observation falling on the receptive eye.” I have the answer. What is the question? Turning an observation inside out, seeking the problem that fits the answer, is the essence of creative discovery. Such circumstances lead the astute investigator to solutions in search of problems and beyond established points of view

Many scientists, including the Harvard physiologist Walter Cannon and, later, the British immunologist Peter Medawar, liked to emphasize how much of scientific discovery was unplanned and even accidental. One of Cannon's favorite examples of such serendipity is Luigi Galvani's observation of the twitching of dissected frogs' legs, hanging from a copper wire, when they accidentally touched an iron railing, leading to the discovery of "galvanism"; another is Hans Christian Ørsted's discovery of electromagnetism when he unintentionally brought a current-carrying wire parallel to a magnetic needle. Rhetoric about the sufficiency of rational method was so much hot air. Indeed, as Medawar insisted in The Art of the Soluble, "There is no such thing as The Scientific Method," no way at all of systematizing the process of discovery. Really important discoveries had a way of showing up when they had a mind to do so and not when you were looking for them. Maybe some scientists, like some book collectors, had a happy knack; maybe serendipity described the situation rather than a personal skill or capacity.
As Robert Root‐Bernstein, physiology professor and author of Discovering, observed,“We invent by intention; we discover by surprise.” In other words, accidents will happen, and it’s a blessing for us that they do.
Serendipity is the way to make discoveries, by accident but also by sagacity, of things one is not in quest of. Based on experience, knowledge, it is the creative exploitation of the unforeseen.

Quinine
The story behind the chance discovery of the anti-malarial drug quinine may be more legend than fact, but it is nevertheless a story worthy of note. The account that has gained the most currency credits a South American Indian with being the first to find a medical application for quinine. According to legend, the man unwittingly ingested quinine while suffering a malarial fever in a jungle high in the Andes. Needing desperately to quench his thirst, he drank his fill from a small, bitter-tasting pool of water. Nearby stood one or more varieties of cinchona, which grows from Colombia to Bolivia on humid slopes above 5,000 feet. The bark of the cinchona, which the indigenous people knew as quina-quina, was thought to be poisonous. But when this man's fever miraculously abated, he brought news of the medicinal tree back to his tribe, which began to use its bark to treat malaria.

Since the first officially noted use of quinine to fight malaria occurred in a community of Jesuit missionaries in Lima, Peru in 1630, historians have surmised that Indian tribes taught the missionaries how to extract the chemical quinine from cinchona bark. In any case, the Jesuits' use of quinine as a malaria medication was the first documented use of a chemical compound to successfully treat an infectious disease. To this day, quinine-based anti-malarials are widely used as effective treatments against the growth and reproduction of malarial parasites in humans.

Smallpox vaccination
In 1796, Edward Jenner, a British scientist and surgeon, had a brainstorm that ultimately led to the development of the first vaccine. A young milkmaid had told him how people who contracted cowpox, a harmless disease easily picked up during contact with cows, never got smallpox, a deadly scourge.

With this in mind, Jenner took samples from the open cowpox sores on the hands of a young dairymaid named Sarah Nelmes and inoculated eight-year-old James Phipps with pus he extracted from Nelmes' sores. (Experimenting on a child would be anathema today, but this was the 18th century.) The boy developed a slight fever and a few lesions but remained for the most part unscathed. A few months later, Jenner gave the boy another injection, this one containing smallpox. James failed to develop the disease, and the idea behind the modern vaccine was born.

Though doctors and scientists would not begin to understand the biological basis of immunity for at least 50 years after Jenner's first inoculation, the technique of vaccinating against smallpox using the human strain of cowpox soon became a common and effective practice worldwide.

Allergy
Charles Robert Richet, a French physiologist, made several experiments testing the reaction of dogs exposed to poison from the tentacles of sea anemones. Some of the dogs died from allergic shock, but others survived their reactions and made full recoveries.

Weeks later, because the recovered dogs seemed completely normal, Richet wasted no time in reusing them for more experiments. They were given another dose of anemone poison, this time much smaller than before. The first time the dogs' allergic symptoms, including vomiting, shock, loss of consciousness, and in some cases death, had taken several days to fully develop. But this time the dogs suffered such serious symptoms just minutes after Richet administered the poison.

Though Richet was puzzled by what had happened, he realized he could not disregard the unexpected result of his experiment. Later, he noted that his eventual conclusions about the dogs' affliction were "not at all the result of deep thinking, but of a simple observation, almost accidental; so that I have had no other merit than that of not refusing to see the facts which presented themselves before me, completely evident."

Richet's conclusions from his findings came to form the theoretical basis of the medical study and treatment of allergies. He eventually proved that there was a physiological state called anaphylaxis that was the antithesis of prophylaxis: When an allergic subject is exposed to an allergen a second time, he or she is even more sensitive to its effects than the first time. Instead of building immunity to the substance through exposure (prophylaxis), the allergic subject's immunity becomes greatly reduced.

In 1913 Richet received a Nobel Prize for his discovery and articulation of diseases of allergy

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.


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
The identification of penicillium mold by Dr. Alexander Fleming in 1928 is one of the best-known stories of medical discovery, not only because of its accidental nature, but also because penicillin has remained one of the most important and useful drugs in our arsenal, and its discovery triggered invaluable research into a range of other invaluable antibiotic drugs.

Alexander Fleming, who was notorious for having the messiest laboratory at London's St.Mary's Hospital. But the chaotic state of his surroundings did not bother Fleming in the least and in 1928 he took off on holiday leaving his lab in a particularly squalid state. On his return he noticed that some mold had contaminated a flu culture in one of his petri dishes. Instead of throwing out the ruined dish, he decided to examine the moldy sample more closely.

Fleming had reaped the benefits of taking time to scrutinize contaminated samples before. In 1922, Fleming had accidentally shed one of his own tears into a bacteria sample and noticed that the spot where the tear had fallen was free of the bacteria that grew all around it. This discovery peaked his curiosity. After conducting some tests, he concluded that tears contain an antibiotic-like enzyme that could stave off minor bacterial growth.

Six years later, the mold Fleming observed in his petri dish reminded him of this first experience with a contaminated sample. The area surrounding the mold growing in the dish was clear, which told Fleming that the mold was lethal to the potent staphylococcus bacteria in the dish. Later he noted, "But for the previous experience, I would have thrown the plate away, as many bacteriologists have done before."

Instead, Fleming took the time to isolate the mold, eventually categorizing it as belonging to the genus penicillium. After many tests, Fleming realized that he had discovered a non-toxic antibiotic substance capable of killing many of the bacteria that cause minor and severe infections in humans and other animals. His work, which has saved countless lives, won him a Nobel Prize in 1945.



X-Rays
X-rays have become an important tool for medical diagnoses, but their discovery in 1895 by the German physicist Wilhelm Conrad Röntgen had little to do with medical experimentation. Röntgen was studying cathode rays, the phosphorescent stream of electrons used today in everything from televisions to fluorescent light bulbs. One earlier scientist had found that cathode rays can penetrate thin pieces of metal, while another showed that these rays could light up a fluorescent screen placed an inch or two away from a thin aluminum "window" in the glass tube.

Röntgen wanted to determine if he could see cathode rays escaping from a glass tube completely covered with black cardboard. While performing this experiment, Röntgen noticed that a glow appeared in his darkened laboratory several feet away from his cardboard-covered glass tube. At first he thought a tear in the paper sheathing was allowing light from the high-voltage coil inside the cathode-ray tube to escape. But he soon realized he had happened upon something entirely different. Rays of light were passing right through the thick paper and appearing on a fluorescent screen over a yard away.

Röntgen found that this new ray, which had many characteristics different from the cathode ray he had been studying, could penetrate solids and even record the image of a human skeleton on a photographic negative. In 1901, the first year of the Nobel Prize, Röntgen won for his accidental discovery of what he called the "X-ray," which physicians worldwide soon adopted as a standard medical tool.

Insulin
Frederick G. Banting, a young Canadian doctor, and Professor John J.R. MacLeod of the University of Toronto shared a Nobel Prize in 1923 for their isolation and clinical use of insulin against diabetes. Their work with insulin followed from the chance discovery of the link between the pancreas and blood-sugar levels by two other doctors on the other side of the Atlantic decades earlier.

In 1889, German physicians Joseph von Mering and Oscar Minkowski removed the pancreas from a healthy dog in order to study the role of the pancreas in digestion. Several days after the dog's pancreas was removed, the doctors happened to notice a swarm of flies feeding on a puddle of the dog's urine. On testing the urine to determine the cause of the flies' attraction, the doctors realized that the dog was secreting sugar in its urine, a sign of diabetes. Because the dog had been healthy prior to the surgery, the doctors knew that they had created its diabetic condition by removing its pancreas and thus understood for the first time the relationship between the pancreas and diabetes.

With more tests, von Mering and Minkowski concluded that a healthy pancreas must secrete a substance that controls the metabolism of sugar in the body. Though many scientists tried in vain to isolate the particular substance released by the pancreas after the Germans' accidental discovery, it was Banting and MacLeod who established that the mysterious substance was insulin and began to put it to use as the first truly valuable means of controlling diabetes.

Isaac Newton, who came up with his theory of gravitation while walking in his garden under an apple tree. We would not have Velcro if it was not for engineer Georges de Mestral taking his dog for a walk and becoming intrigued by the Burdock (Arctium lappa)) seeds that stuck to his dog's coat. Examining the seeds more closely, he saw the possibility of using hooks and loops to bind two surfaces reversibly in a simple fashion. He subsequently developed the hook and loop fastener and patented Velcro in 1951.The baldness drug Minoxidil (marketed as Rogaine) was first developed to treat high blood pressure. But when balding male subjects in a clinical trial starting sprouting new hair, the researchers changed tack and produced a topical treatment for baldness and hair loss. And tretinoin (marketed as Retin A), an acne treatment with a long list of side-effects, is now primarily known for its smoothing effect on wrinkles.

Despite all the examples given, mainstream medical research stubbornly continues to assume that new discoveries will follow exclusively from a predetermined research path.Many in fact,will.Others ,if history is an indication,will not.They will not come from a committee or a research team but from an individual,a maverick who views a problem with fresh perspective.Serendipity will strike and be seized upon by a well trained scientist or clinician who also dares to rely upon intuition,imagination, and creativity.Unbound by traditional theory, willing to suspend the usual set of beliefs,unconstrained by the requirement to obtain approval or funding for his or her pursuits,this outsider will persevere and lead the way to a fascinating breakthrough.Eventually, once the breakthrough becomes part of accepted medical wisdom,the insiders will pretend that the outsider was one of them all along.

As John Barth wrote in the Last Voyage of Somebody the Sailor,”You don’t reach Serendip by plotting a course for it.You have to set out in good faith for elsewhere and lose your bearings serendipitously”.The challenge for educational institutions, government policy,research centers,funding agencies will be how to recognize scientists to lose their bearings creatively.What they discover may just save our lives!