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.