JMS Pearce
Hull, England, United Kingdom

The most exciting phrase to hear in science, the one that heralds new discoveries, is not “Eureka!”, but “That’s funny…” – Isaac Asimov

Horace Walpole (son of the first British Prime Minister, Sir Robert Walpole) coined the word “serendipity” in 1754. It was based on a Persian fairytale in which three princes of Serendip (now Sri Lanka) traveled the world, making discoveries by accidents and sagacity.¹ Serendipity is the faculty of making happy and unexpected discoveries by chance. Scientists often make such discoveries in their investigations, discoveries that are not the products of prediction or expectation.

Of the many such instances in medicine and science,² I shall summarize just a few well-known examples.

Leeuwenhoek’s animalcules

Antonie van Leeuwenhoek (1632 – 1723), a cloth merchant of Delft, developed skill in grinding magnifying lenses and created a simple microscope. In order to test the power of his lenses, he examined many curious objects, animate and inanimate, such as coffee beans, fragments of bees and seeds, and animal tissues. His unexpected findings proved serendipitous, although without a doubt he was consciously exploring the hitherto unknown structure of many cells, tissues, and organisms.

In 1683, he observed “there are more animals living in the scum on the teeth than there are men in a whole kingdom.” He called them animalcules and illustrated the round, rod-shaped, and spiral varieties we know today as cocci, bacilli, and spirochetes.³ He also identified red blood cells, spermatozoa, and protozoa. He published no books but related his discoveries in 190 letters to the Royal Society. In 1680, he was elected Fellow of the Royal Society.

Gram stain

Hans Christian Gram (1853–1938), a Danish bacteriologist, told of his discovery in an original publication in 1884. He stated in a footnote that the method began with the accidental observation that aniline-gentian violet preparations after treatment with potassium iodide solution in alcohol were quickly and fully decolorized. He then tried the method on bacteria and found that some of them took up the crystal violet stain (Gram-positive), and others could not retain the violet stain after the decolorization (Gram-negative). Serendipity had played its part, for he reported, “I was trying to find a double stain for kidney sections with blue nuclei and brown cylindrical casts.” Gram staining was universally adopted to classify bacteria by the staining properties of their cell walls.

Helicobacter pylori

In 1981, the Australian pathologist Robin Warren was surprised to find spiral-shaped bacteria with signs of gastritis in gastroscopic specimens from patients. Barry Marshall learned of Warren’s findings and tried to culture the bacterium, though an initial chart review of Warren’s twenty-seven best cases did not reveal any obvious associations between the bacteria and clinical disease. During the 1982 Easter holiday, agar plates were left in the incubator by mistake. When later inspected, they were found to contain numerous colonies of the spiral bacterium that Warren had observed. This new bacterium associated with peptic ulcers was named Helicobacter pylori.⁴ The findings were not initially accepted, and a frustrated Marshall reported, “I realized I had to have an animal model and decided to use myself.” He drank a culture of Helicobacter to prove that they were pathogenic. Despite serious symptoms, he subjected himself to a gastroscopic biopsy, “the results showing colonies of Helicobacter and classic histological damage to my stomach. This became one of the serendipitous, life changing events in my life.” He recovered and stated, “I had apparently eradicated the Helicobacter myself, without antibiotics, without treatment.”

For patients he prescribed a two-week course of antibiotics and bismuth; the bacteria were eradicated and their symptoms disappeared. What began as Warren’s apparently serendipitous finding was pursued scientifically and proved the causal role of H. pylori. The Nobel Prize in Physiology or Medicine 2005 was awarded jointly to Barry J. Marshall and J. Robin Warren.

X-rays

In 1895, Wilhelm Röntgen was studying cathode radiation, which occurs when an electrical charge is applied to two metal plates inside a glass tube filled with rarefied gas. Although the apparatus was screened off, he noticed a faint fluorescent faint light on a nearby light-sensitive screen. He investigated this happy accident to find a penetrating, previously unknown type of radiation. Objects of different thicknesses interposed in the path of the rays showed variable transparency when recorded on a photographic plate. When he placed his wife Bertha’s hand in front of the rays over a photographic plate, he saw an image of the bones and her ring. This he called a röntgenogram, and because the kind of rays were unknown, he labeled them X-rays. This was the foundational work founded of the field of radiology. Röntgen in 1901 was awarded the Nobel Prize in Physics “in recognition of the extraordinary services he has rendered by the discovery of the remarkable rays subsequently named after him.”

Dicoumarol and anticoagulants

Sweet clover disease of cattle was discovered in the 1920s, but its cause was a mystery. In 1933, Ed Carson, a farmer in Wisconsin, was troubled because his cows were bleeding to death after being fed hay made from spoiled sweet clover. He asked for help from Karl Paul Link, an agricultural chemist, whose experiments with several colleagues showed that the spoiling process in the feed produced dicoumarol, a substance that interferes with the synthesis of vitamin K and prothrombin essential for blood clotting: hence the fatal bleeding. With Mark Arnold Stahmann he crystallized the compound and named it Warfarin (Wisconsin Alumni Research Foundation). Eventually, this accidental observation in cattle led to the use of warfarin as an anticoagulant in human thrombo-embolic disorders.

Viagra

Sildenafil was being studied in clinical trials for the treatment of angina pectoris. Instead of relieving anginal pain, the drug induced unwanted penile erections in some patients. It was marketed as Viagra and became a common treatment for erectile dysfunction.

Radioactivity

In 1857, Abel Niépce de Saint-Victor observed that uranium salts emitted radiation that could darken photographic emulsions. In March 1896, French physicist Henri Becquerel was investigating whether there was any connection between Röntgen’s X-rays and naturally occurring phosphorescent uranium salts that he thought absorbed sunlight and emitted a radiation similar to X-rays. Serendipity then struck. On a dull day, thinking he could not investigate any further without sunlight, Becquerel put his uranium crystals and photographic plates in a drawer. On March 1, he opened the drawer and developed the plates, expecting to see only a faint crystal image. Instead, the image was astonishingly clear. The next day, he reported to the Academy of Sciences that the uranium salts emitted radiation without stimulation from sunlight. He showed that the rays emitted by uranium caused gases to ionize and differed from X-rays in that they could be deflected by magnetic fields. This radiation was not X-ray radiation, but a new phenomenon: radioactivity. Becquerel was awarded the Nobel Prize for Physics in 1903 with Pierre and Marie Curie for their further studies of the Becquerel radiation and initiation of radiotherapy.

Imipramine as antidepressant

The serendipitous discovery of the therapeutic effect of imipramine in depression was the result of a search for a chlorpromazine-like substance for the treatment of schizophrenia.

In 1956 Roland Kuhn, a Swiss psychiatrist, suggested the testing of G 22355 (imipramine hydrochloride), which resembled chlorpromazine. It proved to be ineffective in schizophrenia. Nonetheless, Kuhn tried it in three patients with “vital depressive disposition” and their symptoms improved. Further, in all three patients when the treatment was stopped, symptoms relapsed; this was reversed by resumption of medication. Tricyclic antidepressants flourished despite their fortuitous beginnings. Kuhn somewhat immodestly claimed that “chance” and “good fortune” were only contributing factors.⁵

Penicillin

In 1928, while working on influenza, Alexander Fleming left for a two-week holiday. A Petri dish containing a staphylococcus culture was unintentionally left on a lab bench. When he returned, he found that a Penicillium mold spore had been accidentally introduced into the medium, perhaps through a window.

He observed a clear zone where the mold had created a staphylococcal-free circle. Fleming discovered that the antibacterial substance was produced only by a specific strain of Penicillium – Penicillium notatum – and named the active substance penicillin. His paper published in the British Journal of Experimental Pathology (June 1929) went unheeded. Although he repeatedly suggested its possible value for the treatment of infections in man, not until 1940 did Howard Florey with Ernst Boris Chain and Edward Abraham try to purify and concentrate penicillin, “not in the hope of finding some new antibacterial chemotherapeutic drug, but to isolate an enzyme which we hoped would [inactivate a chemical] common on the surface of many pathogenic bacteria.” After testing in mice and then humans, its antibacterial efficacy was established. “Nature makes penicillin, I just found it; one sometimes finds what one is not looking for,” commented Fleming. Years later, Chain reaffirmed the serendipity: “That penicillin could have a practical use in medicine did not enter our minds when we started work on it…” Penicillin was eventually crystallized by Dorothy Mary Crowfoot Hodgkin (1910-1994) in 1945; she received the Nobel Prize for Chemistry in 1964. The Nobel Prize in Physiology or Medicine 1945 was awarded jointly to Sir Alexander Fleming, Ernst Boris Chain, and Sir Howard Walter Florey.

Serendipity

Unexpected, accidental discoveries occur throughout the realms of science,⁶ medicine, and the arts. Julius Comroe, Jr. wittily observed:

Serendipity is looking in a haystack for a needle and discovering a farmer’s daughter.

But usually, serendipity occurs during a purposeful or deliberate investigation, and thus not entirely by chance. Its genesis is far more complex. It results from identifying “matching pairs” of events that are put to practical or strategic use. It has been suggested that with this definition, serendipity describes a capability, not an event.⁷

Happy accidents only bear fruit when the investigator or observer appreciates their potential significance. Many are probably overlooked or dismissed.

There is a tide in the affairs of men, which, taken at the flood, leads on to fortune… we must take the current when it serves, or lose our ventures. (Shakespeare, Julius Caesar IV)³

Much modern research depends on large teams drawing upon multiple scientific disciplines and using highly technical methods in an environment that promotes the not very creative phenomenon known as “groupthink.”¹ Opportunities for serendipitous discoveries are thereby smothered at source. Metanalyses⁸ and multicenter collaborations neither encourage nor create new ideas. At best, they extend the applications of, or retest preliminary or older ideas, sometimes yielding improvements, but seldom new concepts.

Curiosity, imagination and the recognition of the pursuit of the unusual are necessary ingredients if chance observations are to prove valuable. As Pasteur observed:

Dans les champs de l’observation, le hasard ne favorise que les spirits prepares. [In the field of observations, chance only favors the prepared mind]. 

References

1. Meyers, MA. Happy accidents: Serendipity in modern medical breakthroughs. Arcade Publishing. 2007.
2. Rosenau, M. J. “Serendipity”. Journal of Bacteriology 1935;29 (2):91-8.
3. de Kruif, Paul. Microbe Hunters. New York: Blue Ribbon Books. Harcourt Brace & Company. 1926.
4. Marshall, BJ, Warren JR. “Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration.” Lancet 1984; 1(8390): 1311–1315.
5. Kuhn, R. “The discovery of the tricyclic antidepressants and the history of their use in early years.” A history of the CINP. Brentwood, Tn: JM Productions 1996: 425-435.
6. Roberts, RM. Serendipity: Accidental discoveries in science. New York: Wiley 1989.
7. de Rond, M. “The structure of serendipity.” Culture and Organization, 2014;20:5:342-358.
8. LeLorier, J, Grégoire, G, Benhaddad, A, Lapierre, J, Derderian, F. “Discrepancies between meta-analyses and subsequent large randomized, controlled trials.” New Engl J Med. 1997;337:536–542.