Serendip­ity in Sci­ence

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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