Luria and Delbrück, 1943, Genetics

Here’s the first of my blog posts on “must-read” papers.  I hope others will find these papers interesting and useful.

Luria, S. E., and Delbrück, M.  1943.  Mutations of bacteria from virus sensitivity to virus resistance.  Genetics 28, 491–511.

[I’ve cobbled this post together by borrowing from a couple of previous writings where I explained why the Luria and Delbrück’s experiment is my all-time favorite.  One of these earlier pieces was a Q & A in Current Biology (2003); the other was an essay that appeared in Microbe (2011) and then in the book Microbes and Evolution: The World That Darwin Never Saw (2012).  I’ve also tweaked the text and added some bits to make things flow.]

Short summary:  An elegant experiment — sometimes called the “fluctuation test” — by Salvador Luria and Max Delbrück showed that new mutations that made bacteria resistant to phage (viruses that infect bacteria) arose before the bacteria were exposed to the phage.  This paper removed the specter of Lamarckian inheritance from microbiology, and it set the stage for the tremendous advances in microbial genetics and molecular biology that took place over the next several decades.  Theirs was a beautifully simple, yet subtle, experiment on a fundamental concept.

Personal influence:  I first read about Luria and Delbrück’s paper as an undergraduate at Oberlin College, in a course taught by Richard Levin using Gunther Stent’s 1971 textbook, Molecular Genetics: An Introductory Narrative.  Stent took a historical approach to microbial and molecular genetics by emphasizing the ideas, questions, and experiments that led to the growth and success of those fields.  I remember the challenge of reading about Luria and Delbrück’s experiment, trying to wrap my head around how it worked and what it meant, and then the wonderful “Aha!” moment when I got it.

But I did not go directly on to work with microbes.  Instead, I did my Ph.D. in zoology, with my dissertation research on ground beetles in the mountains of western North Carolina.  Despite the pleasures of working outdoors, the research was slow, heavy rains often drowned the beetles in my pitfall traps, and it was difficult to imagine feasible experiments that would really test the scientific ideas that most excited me.  So as I pondered future directions, I recalled the Luria and Delbrück experiment that I had encountered as an undergraduate.  I remembered not only its elegance, but also the profound insight it gave into the tension between randomness and direction in evolution — a tension that continues to fascinate me and lies at the heart of the long-term evolution experiment in my lab.

It wasn’t until I was a postdoc, learning how to work with bacteria, that I actually read the Luria and Delbrück paper.  It’s not an easy paper to read.  If the experiment is unfamiliar to you, then you might want to read about it before reading the original paper.  Pages 556-558 in Sniegowski and Lenski (1995, Ann. Rev. Ecol. Syst.) briefly explain the experiment.

Historical perspective:  The science of genetics took hold with the rediscovery of Gregor Mendel’s experiments on pea plants in the early 1900s.  However, microbiologists remained baffled by the question of heredity in bacteria for several more decades.  They saw that bacteria could “adapt” to various challenges, but they couldn’t tell whether spontaneous mutants had appeared and been selected or, alternatively, whether the challenge had induced the cells to change themselves.  In 1934, a microbiologist, I. M. Lewis, wrote that “The subject of bacterial variation and heredity has reached an almost hopeless state of confusion . . . There are many advocates of the Lamarckian mode of bacterial inheritance, while others hold to the view that it is essentially Darwinian.”  And in 1942, Julian Huxley wrote Evolution: The Modern Synthesis and explicitly excluded bacteria from the then-modern synthesis on the grounds that “They have no genes in the sense of accurately quantized portions of hereditary substance …”

This confusion cleared the very next year with the publication of what is, to me, the single greatest experiment in the history of biology.  Working together, Luria, a biologist, and Delbrück, a physicist-turned-biologist, employed subtle reasoning and an elegant design to demonstrate that some mutations in E. coli occurred before the selective challenge was imposed, and therefore the mutations could not have been caused by the challenge.  In other words, mutations are random changes that occur whether or not they prove useful, while selection provides the direction in evolution by disproportionately retaining those mutations that are advantageous to their carriers and discarding others that are harmful.

Luria and Delbrück’s paper launched a tidal wave of research that led to the discovery of DNA as the hereditary material and to cracking the genetic code.  But it had little immediate impact on evolutionary research.  The new molecular biologists pursued their reductionist methods, while evolutionary biologists, grounded in natural history, didn’t want to study things they couldn’t even see.  These naturalists preferred beautiful butterflies and even homely fruit flies to E. coli that, after all, come from a rather uninviting habitat.

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29 Comments

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29 responses to “Luria and Delbrück, 1943, Genetics

  1. I started a series many years ago on my blog which I did not really continue much on “Classic papers in genetics and evolution that are available in Pubmed Central”. As the first paper I chose — Luria and Delbruck 1943. – See the post here: http://phylogenomics.blogspot.com/2006/12/classic-papers-in-genetics-and.html

    • Thanks, Jonathan. I started to make a joke about “great minds think alike”. But the real message is “great papers have an impact.”

    • rbeagrie

      I think it’s very unfair to Delbrück to say that his “direct contribution to cracking the genetic code was pretty much non-existent”. He was a central member of the group of molecular biologists who were interested in this problem (for example, he was a member of the RNA tie club http://en.wikipedia.org/wiki/RNA_Tie_Club). His work inspired Schrödinger to write his highly influential 1944 book “What is life?”, which in turn was cited by Crick as his inspiration for moving from Physics to biology. As a more concrete example, his 1954 paper “On the replication of Desoxyribosenucleic acid” (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC534166) brought up some major issues with the model proposed in Watson and Cricks Nature paper, and was a big part of the reason why Meselson and Stahl’s famous demonstration of the semi-conservative replication of DNA in ’58 was so important for the field.

      For anyone interested in the work of the phage group, especially within the wider context of the birth of modern molecular biology, I can’t recommend Freeland Judson’s book “The Eighth Day of Creation” highly enough. It’s amazing how much cross-talk there was between people like Luria and Delbrück in the US, Crick and Brenner in the UK and Jacob and Monod in France.

    • Note to readers: I think that Rob Beagrie’s comment above is a reply to Matthew Cobb’s comment below (not to Jonathan Eisen’s comment).

      And thank you, Rob, for calling readers’ attention to Horace Judson’s superb book and other critical steps in the history of the field.

  2. Matthew Cobb

    Very nice article! And thanks for the other link @phylogenomics! I look forward to the rest of your ‘must read’ posts.

    One nit to be picked: You write “Luria and Delbrück’s paper launched a tidal wave of research that led to the discovery of DNA as the hereditary material” Not quite true, as Avery had already demonstrated this (and both Delbrück and Luria knew of his findings in spring 1943, although as Delbrück admitted he ‘didn’t know what to do with it’) – Avery et al’s paper was published in January 1944.

    You can certainly argue that the Luria and Delbrück was important in the development of the ‘phage group’, although their direct contribution to cracking the genetic code was pretty much non-existent, and even in 1953 when Hershey presented his ‘blender experiment’ data at CSH he was still assuming that proteins played a role in inheritance… http://whyevolutionistrue.wordpress.com/2013/06/06/another-dna-anniversary-which-tells-a-different-story-from-the-textbooks/

    • Thanks, Matthew, for filling in a little more of the history. I didn’t mean to imply that L&D or the phage group *figured out* everything that “led to the discovery of DNA”, etc. But I do think their paper “*launched* a tidal wave of research” by showing that bacteria had genetic inheritance that was experimentally tractable.

  3. Something that frustrates me so much is how new students do not understand the context of these original experiments. I mean, I have colleagues tell me that their students “understand” this paper, and I can promise you—having taught those students—it is not true.

    A few years ago, I talked a student into doing something really pretty icky. She did portions of this experiment, showing that rifamycin resistant bacteria were present *before* being plated on the drug containing media, using replica plating. It wasn’t great I had to use VERY crowded plates. But it did work.

    Thanks not only for the paper, but also for your essays about it.

    I should bug you about doing a podcast for my class—what five papers do you think every microbiologist should read, and why? I know you are a busy man. Maybe for MicrobeWorld video? Because I promise you, Rich, students react very well to effective speakers…which you are.

    • On “understanding” the L&D paper, I can sympathize with the students. One has to *want* to understand it, and that means one must really want to understand how the world works. For some, that’s a core value but, alas, for many (old and young) … nope.

      Kudos to you and the your student for undertaking the L&D-style experiment in the lab!

    • Lots of things that students have been told to accept as true are not clear, or haven’t been looked at carefully. I once had a student who asked me what the mortality rate of bacteria when frozen in glycerol was…and I realized I just didn’t know. A little independent project was born.

      I think you did something related to this…

  4. John Dennehy also picked this paper as one of his classics: The Fluctuation Test.

  5. I’ll be teaching this experiment during the next couple of weeks in microbial genetics Rich. I don’t think the students really understand the controversy of the time so I might sprinkle in some of your quotes.

    On a side note, I feel that “simple” experiments are often frowned upon by various federal funding agencies with the NSF being the prime culprit. I have heard (and experienced) that grants with complex systems biology and computational modeling of systems are heavily favored for funding right now. I am in no way against these experiments, but I think we need to leave room for the simply designed, yet elegant experiments that can reveal fundamental insights, as evidenced by Luria and Delbrück and your own LTEE.

    • Feel free to quote me, of course. But I’m not sure it will help. Next favorite paper I’ll post on (I think) might get more attention from pre-meds.

      Interesting take on science funding. And thanks for the kind words about LTEE.

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  7. Frank Schmidt

    Great post. I, too, read this as a postdoc, and go back to it at least once a year. George Smith at Missouri has reproduced the L-D experiment (using yeast) in his lab course for freshmen in our Math-Life Science program. It’s the best introduction to Mathematical Biology I can think of. I’m looking forward to the next ones to see if your list of essential papers corresponds to mine. Cheers.

  8. Frank Schmidt

    Please email me privately f.schmidt AT mchsi.com, and I can put you in touch with George. Or you can look him up on the web. Frank

  9. W.Benson

    There is also the larger issue as to why science in general did not look on randomness, in its Darwinian meaning, as a null hypothesis, put onus of refutation on proponents of directed variation. One answer, IMHO, is that establishment science was churchy and not too keen on accepting unplanned or unprogrammed evolutionary change. Students would be wise to look at how core views in science have shifted over the past couple of centuries.
    Another accessible review is provided by R. Rayaraman, 2008 (Aug), “Joshua Lederberg’s Legacy,” Resonance, pp. 716-719.

  10. Reblogged this on Tropical Bioinformatics and commented:
    R. Lenski talk about the fluctuation test (Luria/Delbrück experiment), very interesting!

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  12. I am looking forward to more posts in this series! These are very useful to people wanting to move from mathematics to biology.

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