Published ahead of print on May 13, 2005, doi:10.1164/rccm.200503-436OE
© 2005 American Thoracic Society doi: 10.1164/rccm.200503-436OE
Voltaire, Walpole, and PasteurVariations on the Theme of DiscoveryUniversity of California–San Francisco, San Francisco, California Correspondence and requests for reprints should be addressed to John F. Murray, M.D., International Union against Tuberculosis and Lung Disease, 68 Boulevard Saint Michel, 75006 Paris, France. E-mail: johnfmurr{at}aol.com The purpose of this essay is to show how Voltaire (born François Marie Arouet), Horace Walpole, and Louis Pasteur—illustrious men from greatly differing backgrounds and professional accomplishments—characterized the process of discovery, each placing particular emphasis on various permutations among three fundamentals: keen observation, brilliant deduction, and fortuitous accident. To illustrate the value of the resulting interpretations, I'll provide some examples of how certain discoveries were made that influenced science and medicine, and how other opportunities were missed and their benefits delayed. VOLTAIRE I knew about Voltaire (Figure 1) and had read Candide before I started medical school, but I had never heard of Zadig. The classwide introduction to this remarkable man, Zadig, came during our first lecture in surgery, and it made quite an impression. (Thinking about it now, that session may have been the best surgical experience I ever had.) At that point in our curriculum, every afternoon started with a lecture; so we were all milling around the upper rows of an old amphitheater, chatting in typical postprandial medical student fashion, when suddenly, down below us, in strode an imposing man, ramrod straight with lots of wavy gray hair and eyebrows to match, and a starched white coat straining against his portly belly. It was a good entrance that commanded instant silence and riveted our attention. Without a word of introduction, Professor Frederick Reichert sat down at the lone desk and proceeded to read from Zadig, or Destiny, an Oriental Tale, one of the earliest of Voltaire's moral fables (1).
In chapter 3, "The Dog and the Horse," Zadig, a well-educated and wise young man, is strolling in the countryside near Babylon when he encounters one of the queen's eunuchs followed by several officers of the guard who are searching for the queen's dog. When questioned, Zadig replies, "It is a bitch, not a dog," and then goes on to describe the animal in great detail. "‘Then you have seen her,’ said the chief eunuch, quite out of breath." To the eunuch's surprise, Zadig answers, "No," and denies ever having seen the animal. Moments later, Zadig runs into the chief huntsman and other palace officers, who are frantically looking for the finest horse in the king's stable, which had broken loose and escaped. Once again, Zadig provides an accurate description of the animal, and then avows he has never laid eyes on it. Voltaire writes, "The chief huntsman and chief eunuch were in no doubt that Zadig had stolen the King's horse and the Queen's bitch." So, Zadig was arrested and sentenced to be flogged and exiled. But both animals soon turned up, so the sentence was changed to a fine of 400 ounces of gold "for having declared that he had not seen what he had seen." After paying the fine, Zadig describes how he inferred from the tracks of the animals and other evidence he noticed along the road the size and condition of both the bitch and the horse, and in such detail that his inquisitors believe he must surely have seen them. That is where the professor stopped reading; then he looked up, closed the book, and walked slowly out of the room—not another word. I didn't learn until much later that there was actually more to the story and that Reichert had quit, deliberately, before the chapter ended. It turns out that, after hearing about Zadig's feats of scrutiny, the king of Babylon commanded that the fine be repaid; however, that sum and more were extorted by clerks and functionaries in the transactions. Thus defrauded, "Zadig saw how dangerous it sometimes is to be too clever." Although Voltaire really had a cynical denouement in store for Zadig at this point (it works out happily at the end), we impressionable medical students were disconnected from the plot after being purposefully dazzled by how much can be learned through careful perception and thoughtful deduction (not, actually, traits I associate with many of my surgical colleagues).
Archimedes et al. In much the same category are Isaac Newton's instant grasp of gravity after the proverbial apple bounced off his head and James Watt's divining the force of steam while watching a vigorously boiling kettle of water and observing its lid popping up and down. (Actually, Watt did not invent the steam engine, as many of us were taught, but he did get the idea that allowed him to turn the existing inefficient prototypic engine into the machine that powered the industrial revolution.)
Servetus WALPOLE Voltaire was one of the great personages of the 18th century: philosopher, satirist, playwright, opinion-giver, and friend of kings and nobles throughout Europe. But Voltaire's views were not uniformly welcomed, much less accepted; he was disliked by Louis XV of France, detested by his rivals, and disdained by religious authorities (whom he railed against). In contrast, Horatio (Horace) Walpole (Figure 2), the youngest son of former prime minister Sir Robert Walpole, was an effete aristocrat, an undistinguished member of parliament, who succeeded to the earldom of Orford in 1791, 6 years before his death. Connoisseur, collector and novelist, Walpole was much admired during his lifetime for his Gothic horror tale, the Castle of Otranto; today, he is celebrated chiefly for his letters, hundreds of which were sent over a 45-year period to his good friend and distant cousin, Sir Horace Mann, who spent many years as British minister to the court of Florence. On January 28, 1754, Walpole wrote to Mann to acknowledge the arrival in England of a portrait Mann had sent to him, and also to recount a "critical discovery" he had made concerning the heritage of the lady featured in the painting (3):
This discovery, indeed, is almost of that kind which I call Serendipity, a very expressive word, which, as I have nothing better to tell you, I shall endeavour to explain to you: you will understand it better by the derivation than by the definition. I once read a silly fairy tale, called the three Princes of Serendip: as their Highnesses travelled, they were always making discoveries, by accidents and sagacity, of things which they were not in quest of. Walpole's "silly fairy tale" had a real name: The Travels and Adventures of Three Princes of Sarendip, who were the sons of Jafer, the philosopher-king of Sarendip (or Serendib), ancient names for what is now Sri Lanka. According to the exhaustive analysis of Robert Merton and Elinor Barber (3), the princes had many adventures and made astounding discoveries as they went on their journeys, through their "careful observations and subtle inferences." There is a Zadig-like episode in which the princes meet a camel driver who has lost one of his animals, which they are able to describe precisely from clues they had spotted earlier as they rode along. Voltaire is believed to have read the tale about the three princes and, indeed, was accused of having plagiarized the camel story; clearly, he used a similar description-in-absentia event to illustrate Zadig's exceptional powers of observation and deduction, but that kind of metaphor, in various guises, was already well known and no one took the charge seriously. After Walpole died, his word-child languished in his copy of the letter to Mann in which it was first composed; "serendipity" remained concealed from the world until 1833, when the Mann correspondence was published in London. Though Walpole's expressive coinage was placed before the public and may have been used in private discourse, it didn't appear in print by another writer until 1857, when it became an increasing part of the vocabulary of book collectors and readers (4). "Serendipity" made it into the Oxford English Dictionary in 1913. A second reference to serendipity in Walpole's letters was noted by Richard Boyle (5), in 1980, while reading the correspondence in a London library. In a letter to Hannah More, an eminent social activist and religious reformer, Walpole wrote, "nor is there any harm in starting [flushing out] new game to invention; many discoveries have been made by men who were à la chasse of [hunting for] something very different." Although Walpole didn't use the word, the editor of his letters did, in a footnote that says, "Horace Walpole coined the word ‘Serendipity’ to describe this process [my emphasis]." "This process" adds the new wrinkle that serendipitous, accidental discovery can occur not only while passively going about your business (Zadig-like) but while actively searching for something else. The editor's embellished version is the one that has long prevailed in science and medicine, and includes the twin concepts of "looking for one thing and finding another" by "happy accident and reflection": a bit of an exaggeration of what actually befell the three princes of Sarendip as they journeyed from one exotic place to another. But as Walpole clearly stated, serendipity also has boundaries: you can't set out deliberately looking for something and find it serendipitously; if, however, your search turns up something else that you weren't seeking and that you're glad to have, that's serendipity at its mightiest. (Julius Comroe interpreted serendipity in this fashion when he defined it as "looking for a needle in a haystack and finding the farmer's daughter.")
Eriksson and Gross
It started with a meticulous analysis by C. B. Laurell and his research fellow, Sten Eriksson (6), of the results of measurements of the amounts and types of proteins circulating in the bloodstreams of a large number of people living in southern Sweden. They discovered a previously unknown dysproteinemia, a marked reduction in one of the main components of the electrophoretic Unexpectedly and independently of Eriksson's work, in 1964–1965, Paul Gross and his team of investigators (7, 8) noticed that emphysema developed in the lungs of rats into which they had instilled papain, a potent plant enzyme with a broad spectrum of proteolytic activity. This finding was classic serendipity: Gross was not trying to produce emphysema, he was hoping to attenuate the harmful effects of another kind of injury he was studying. But emphysema is what developed, and Gross recognized the importance of this fortuitous finding, which opened up an entirely new field of emphysema research in experimental animals. PASTEUR From Walpole's coinage of serendipity, we need to fast-forward almost exactly 100 years, to December 7, 1854. On that day, in his inaugural lecture as professor and dean of the faculty of science at the University of Lille, Louis Pasteur (Figure 3) told his audience, "Dans les champs de l'observation, le hazard ne favorise que les esprits préparés [emphasis added]," which means, "In the fields of observation, chance favors only prepared minds" (9). In other words, Pasteur was encouraging scientists to prepare their minds well to be ready for those random lucky events that crop up from time to time.
But Pasteur seems also to be saying that "sagacity," as used by Walpole in his letter to Mann in which he defined serendipity, isn't good enough: sharp observations and high-powered deductions won't get the job done every time; specially attuned minds are necessary. Disappointingly, Pasteur, one of the best minds in the business, didn't tell us how to achieve that special state. Other scientists, though, have thought about what it takes and offer some advice: knowledge in depth and breadth come through as prerequisites, but "curiosity," a mixture of wonder and openness, seems to be a key ingredient of accidental discoveries (10). Less attention has been directed to the other side of Pasteur's coinage, which sounds almost like a self-fulfilling prophecy: minds that come through when the opportunity presents itself are "prepared"; those that fail are not. Regrettably, that simple fact turns out to be true.
Fleming
Missed Opportunities Another missed opportunity involved Selman Waksman, one of the world's best soil microbiologists, who won the Nobel Prize for the 1944 discovery of streptomycin, considered the first powerful antituberculosis agent (13). (Streptomycin was actually discovered by one of Waksman's graduate students, Albert Schatz, who not only found the strain of Streptomyces griseus that elaborated the antibiotic but performed the Herculean task of extracting it for microbiological testing and analysis; Schatz's contribution was ignored by the Nobel committee, which ignited a rancorous dispute between the two men [14].) According to Comroe (12), in 1932, Waksman passed up the chance to study a culture plate of dead Mycobacterium tuberculosis, apparently killed by a contaminating fungus or other microorganism (perhaps a Streptomyces) growing on the medium, which was handed to him by his pathologist friend F. R. Beaudette. CONCLUSIONS
Although Voltaire, Walpole, and Pasteur—philosopher, man of letters, and scientist—each emphasized what he believed mattered most in making discoveries (and there is a certain evolution in their thinking), all three pronouncements contain the basic elements of careful observation, brilliant deduction, and happy accident. The examples I selected also demonstrate the overlap in the process of discovery. Archimedes' and Newton's breakthroughs had hints of serendipity, though neither was actively at work (their minds probably were) when they stumbled on the answers they were seeking: the former was taking a bath, the latter dozing under an apple tree. Laurel and Eriksson were as much exemplars of Voltaire as they were of Walpole: they were hoping to find something when they found "it" ( FOOTNOTES Conflict of Interest Statement: J.F.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. Received in original form March 20, 2005; accepted in final form May 9, 2005 REFERENCES
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