Mike the Mad Biologist

Serendipity, Picking the Right Strain, and the Foundations of Modern Molecular Biology

Posted by Mike on May 26, 2011
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A seminal discovery of modern biology was Joshua Lederberg’s demonstration that bacteria can swap genes through a process known as bacterial recombination. Not only is recombination the mechanism by which antibiotic resistance genes are transferred, but it’s also been turned into a useful tool for genetically manipulating E. coli, which has led to so many things, including the industrial synthesis of insulin; it’s also a key tool–and at one time–the key tool for molecular genetics.

So while working my way through Population Genetics of Bacteria: A Tribute to Thomas S. Whittam, I came across this fascinating footnote in a chapter by microbiologist and population geneticist Bruce Levin about Lederberg’s key discovery (italics mine):

Joshua Lederberg also knew how rare recombination is in E. coli. Had he worked with any of the other then prominent laboratory strains…or almost any wild strain, he would have gotten negative results in his 1946 experiments testing for recombination in this bacterium. The strain he used, E. coli K-12, was an oddball. It bore a plasmid, F, which was permanently derepressed for conjugative pili synthesis and a chromosome with insertion sequences homologous to those on the plasmid which enabled this conjugation-encoding accessory element to integrate into the chromosome by Rec-mediated recombination. I once asked Josh how many other strains he would have looked at if he had gotten negative results with K-12. He told me, “One.” Lederberg and Tatum’s preparation to do these experiments, generating the amino acid and fermentation negative mutants, was a considerable task at the time. What a combination: serendipity and a prepared, brilliant mind!

I have the impression that people who aren’t scientists often think there is this huge implacable juggernaut that will inevitably discover what needs to be discovered. But so many key discoveries are actually very serendipitous.

Kinda humbling.

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Comments

  1. #1 Comrade PhysioProf
    May 26, 2011

    My ability to launch an independent career was in large part dependent upon the completely chance event of a particular individual joining the faculty in the department where I was already a post-doc in my mentor’s lab.

  2. #2 JohnV
    May 26, 2011

    Yeah my PhD was mostly earned through characterization of a phenotype that was observed by chance in a bacteria that had been studied for over 100 years without it being noticed.

  3. #3 hibob
    May 26, 2011

    “I have the impression that people who aren’t scientists often think there is this huge implacable juggernaut that will inevitably discover what needs to be discovered. But so many key discoveries are actually very serendipitous.”

    Recombination had already been observed in E. coli. Why wouldn’t it have been studied by someone else if Lederberg had picked the wrong strain?

    In fields like microbiology, resources (knowledge, technology, and the number of people with the talent to make use of both) increase rapidly year after year. Lederberg’s discovery was definitely serendipitous in ’46, but would have been very low-hanging fruit by the early ’50′s if no one else had worked it out by then.

    For the big picture, implacable juggernaut covers a lot of it. For individual careers: Chance favors the prepared mind, FTW.

  4. #4 Evil Fruit Lord
    May 28, 2011

    This just made me think of another example from my field, fruit breeding:

    Not so long ago all fresh blueberries were grown in a fairly short window in the summer. This was spread out some by different geographies and varieties (and replicated in the southern hemisphere) but there was a huge chunk of the spring and fall had no production, making blueberries a purely seasonal crop, because the plants just were not adapted to warmer climates, where they would have been able to produce earlier in the year.

    In the 1950s, a breeder at the University of Florida, Ralph Sharpe, tried to remedy this by making crosses between the standard highbush blueberry, Vaccinium corymbosum, with the native Vaccinum darrowi. V. darrowi is diploid, and hardly looks like a blueberry, while V. corymbosum is tetraploid. Blueberries have a very strong triploid block, so normally when you make this cross, you don’t even get sterile triploids, you just get nothing–the seeds don’t even germinate. Sharpe chose two wild selections of V. darrowi and made crosses..

    And one of those selections, Florida 4B, successfully produced a fair amount of viable seedlings, and then to everyone’s surprise, those seedlings proved to be fertile…and that was the basis of the southern highbush blueberry, which has been bred from a core of material all based on those Florida 4B crosses. If you eat blueberries in the spring or fall, you’re eating the offspring of Florida 4B.

    Many years later it was determined that Florida 4B is incredibly unusual in that it happens to produce a huge proportion of unreduced gametes. Rather than non-viable triploids, the offspring were all tetraploids. If any other selection (like the one other one used) had been chosen, they’d have gotten nothing. It would have become accepted wisdom that you couldn’t cross V. darrowi with V. corymbosum…

    Some one might well have tried it again in the next fifty years, and maybe they’d have gotten lucky enough to select Florida 4B or something like it. Or probably some a determined person could have brute-forced it, made lots of crosses, and gotten some unreduced pollen out of something else. But there are over a hundred Vaccinium species, and there are lots of crosses that we all just accept as not being options that have only been tried a few times–no one likes to waste their time on things other people already found didn’t work.

    Year round production has really transformed the blueberry industry, resulting in huge growth in the last decade or two. Maybe not on the same level as bacterial recombination, but nonetheless a piece of serendipity in science that has significant real world impacts.

  5. #5 Şis Örgü
    May 29, 2011

    “I have the impression that people who aren’t scientists often think there is this huge implacable juggernaut that will inevitably discover what needs to be discovered. But so many key discoveries are actually very serendipitous.”
    Recombination had already been observed in E. coli. Why wouldn’t it have been studied by someone else if Lederberg had picked the wrong strain?
    yes comenet Sis Örgü

  6. #6 totto
    May 30, 2011

    What makes a good biologist?