by Roberto
Serendipity. I feel it is one of the most beautiful words in English; it's so melodic and loaded with meaning. Perhaps I'm fascinated by it because it is difficult to translate into my native Spanish. Regardless, it does seem that quite often scientific discoveries happen serendipitously. At Memo Berkmen's behest (STC readers will recognize Memo as a long-time friend of the blog) today I'm delving into this theme of serendipity in science. And a good place to start is to describe both its meaning and etymology.
Fig. 1. The Three Princes of Serendip from an old Persian manuscript. Source
Thanks, Memo, for pointing me in the direction of this fascinating origin-of-word history! Serendipity is one of those few words for which you can pinpoint exactly the day it was invented. It was first used in a letter from Horace Walpole (English writer and art historian) to Horace Mann (English diplomat in Florence) dated January 28, 1754. Walpole was inspired by the ancient Persian fairy tale The Three Princes of Serendip, Serendip being the Persian name for the island of present-day Sri Lanka. Walpole writes that the princes of the tale "were always making discoveries, by accidents and sagacity, of things which they were not in quest of." By way of example Walpole recounts how one prince "discovered that a mule blind of the right eye had travelled the same road lately, because the grass was eaten only on the left side, where it was worse than on the right." The key distinction from mere accident, coincidence, or good fortune is that serendipity involves sagacity. When you think sagacity, think keen perception, acuteness of mind, wisdom even. In other words, a prepared mind. It was one hundred years later, in 1854, that Louis Pasteur said "...dans les champs de l’observation le hasard ne favorise que les esprits préparés" (...in the fields of observation, chance only favors prepared minds) when describing Ørsted's presumed serendipitous discovery of electromagnetism. But, enough on word history and meaning. Now microbes enter the stage.
Fig. 2. Original culture plate in which penicillin was observed. Source
When it comes to the history of microbiology, there is little doubt that the best known example of a serendipitous discovery is Alexander Fleming's chance observation of a Penicillium contaminant killing adjacent colonies of Staphylococcus followed by the discovery of penicillin, as described in Mechas' post on contamination. It is difficult to overstate the importance to humankind of Fleming's discovery and the subsequent development of penicillin as a clinically useful antibiotic. From what we know of Fleming, can we venture a guess as to what might have led him to have a "prepared mind" that allowed him to go from chance observation to serendipitous discovery? That, of course, is a Talmudic Question with no right answer. We'll never know for sure. But in an enthralling essay, Robb Dunn offers an attractive possibility. Yes, Fleming was known for being a messy worker, leaving stacks of plates around for weeks on end, not necessarily an attribute to prepare his mind. But Fleming also painted, he was a member of Chelsea Arts Club where he focused on watercolors. And, he also took a liking for painting with microbes! In doing this he might have developed a keen sense for observing what grew on his Petri dishes. Where others might have seen a contaminated plate to throw away, Dunn speculates that Fleming saw a version of one of his paintings: "Each of the colonies of Staphylococci bacteria that he had inoculated on the plate had grown into a small shape resembling a planet or a star in a night sky. But there among his wild planets was something else, a larger, lighter body at the top of the dish, the Penicillium fungus. Around it the sky was dark, where the bacteria were dying. It was his masterpiece, his 'rising sun,' the painting that would save more lives than any other discovery." I like the idea that Fleming's melding of the worlds of art and science played an important role in preparing his mind.
Another example of serendipity in microbiology involves the model bacterium Escherichia coli. Given that I spent more than half of my career immersed in E. coli research, this one is near and dear to my heart. In a prior post, "How E. coli Rose to Prominence," I described how the influential Phage Group, led by Max Delbrück, played a critical role in the early days of molecular biology. Then in last Thursday's post, Mechas described the role that sewage played in the isolation of the phage that was used by Ellis and Delbrück in their landmark paper showing the step growth of phages. She ended her post with the question: Why did Emory Ellis choose E. coli as the host to go searching for phages in the Pasadena sewers? Simply because Carl Lindegren, a student working with Neurospora crassa in Thomas Morgan's lab at Caltech – where Ellis was working – happened to have a strain of E. coli. That's luck, that's the accident. But I think Ellis' wanting to study viral growth in a simpler system – bacteriophages – to understand cancer, and his realization that such an easy-to-grow bacterium as E. coli would be advantageous to use as a host for phages, that was his sagacity, his prepared mind. Kudos to Ellis for his serendipitous choice!
Fig. 3. Live (yellow) and dead (green) E. coli cells stained with acridine orange after five days in stationary phase. Image credit: Mechas Zambrano
In bringing up serendipity, Memo concluded with this statement: "I was therefore wondering if you would be interested in digging into your past experiences of serendipity and share a story at STC?" It's certainly humbling to claim a serendipitous finding of one's own in the shadow of discoveries that ushered in the antibiotic era and molecular biology! But the point is important, serendipity can play a role in the science that we all perform, it's not restricted to earthshattering discoveries. So, here it goes.
During the mid-1980s, my lab became interested in the changes that E. coli underwent during stationary phase. Initially we kept our cultures for hours in stationary phase. Then we started incubating them for several days, weeks even. Viable counts remained constant for a couple of days, followed as expected, by an exponential death phase. Then came the surprise, after a couple of days of rapid death, after about 99% of the cells had died, the death rate slowed down to almost zero. Some might have disregarded the small fraction that remained alive. Instead, we were curious. Many questions came up: What's keeping them alive? Why won't they die? Have they entered a death-resistant program? Apparently, our minds were prepared; we somehow knew that the phenomenon was worth investigating. As it turns out, if we had used a different growth medium, we would not have observed such dramatic reduction in the death rate. Indeed, this was a chance observation. But by pursuing it, we went on to discover that the remaining viable cells were mutants that could grow during stationary phase. Their growth advantage in stationary phase – we termed their phenotype GASP – was so great that they took over the population in a matter of a few days. We were witnessing very rapid evolution in stationary phase cultures! Stationary phase turned out to be anything but stationary, and GASP came to be seen as a general phenomenon in microbial evolution. Were we sagacious? Does this discovery qualify as serendipitous? You be the judge.
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