Matthew Meselson (1930-) is a molecular biologist and geneticist. He is best known for the Meselson-Stahl experiment, which he carried out with Franklin Stahl at Caltech in 1958. To understand the signficance of Meselson’s work, and why the CSHL Library & Archives is so thrilled to have this collection, it’s worth going into some detail about this legendary experiment.
In the late 1950s, the process of DNA replication was not yet fully understood. There were three competing models. First, there was the conservative model, in which the entire original double helix served as a template for an entirely new double helix. Then, there was the semi-conservative model, proposed by Watson and Crick, in which the original double-stranded DNA helix separated, and each strand received a newly-synthesized complementary strand, resulting in two new double helices each composed of 50% old and 50% new material. Finally, there was the dispersive model, which resulted in two double helices in which sections of original and newly synthesized material alternated in a regular pattern.
To determine which of these three models was correct, Meselson and Stahl grew E. coli in a medium with a heavy isotope of nitrogen (DNA contains a lot of nitrogen). Soon they had E. coli with, effectively, heavy DNA. They then took some of these E. coli and allowed them to reproduce in a medium with normal nitrogen. This gave them several distinct generations of E. coli, each with a subtly different with a mixture of heavy and normal DNA, which they could extract to use in their experiment. But how, you might ask, did the difference between heavy and normal DNA help them determine which of the three models of DNA replicaiton was correct?
The key tool for this experiment was the centrifuge — specifically, a slick new model in the lab of Caltech biotechmist Jerome Vinograd which allowed researchers to photograph the contents while the machine was spinning. Meselson and Stahl made a cesium chloride solution with a density that would allow DNA to hang suspended in the solution, neither floating to the top nor sinking to the bottom. They put this solution into a tube and the tube into the centrifuge. When they spun it at the correct speed for a few hours, this created a salt gradient within the fluid in the tube, with a density that increased toward the outward end of the tube. The centrifuge process also caused other materials present in the solution — specifically, the DNA of their E. coli — to separate out by weight, forming bands that could be photographed and analyzed.
Control samples composed entirely of heavy DNA and entirely of normal DNA formed bands at two distinct points on the tube. The researchers repeated this process with DNA from the first generation of E. coli whose heavy DNA had been allowed to replicate in medium with normal nitrogen. The first generation of E. coli, in other words, whose DNA included a combination of heavy and normal nitrogen.
The DNA of these E. coli formed a band in the center between the heavy and the normal points. This ruled out the conservative model. Had this model been correct, this first-generation DNA would have been composed of old strands of entirely heavy DNA and newly synthesized strands of entirely normal DNA, with nothing in the middle.
Centrifuging the DNA of subsequent generations produced bands consistent with some strands of DNA that were half ‘heavy’ and half regular and an increasing proportion of strands that were entirely regular. This ruled out the dispersive model. Had this model been correct, there would have been only one ‘middle’ mixed band, however many generations were measured, since the heavy DNA would have been distributed evenly among all the strands.
The results, in other words, were consistent with the semi-conservative model, which subsequent research by many others over the years has confirmed to be the correct one. The Meselson-Stahl experiment is famous for helping biologists resolve the question of how DNA replication works. It’s also famous for its clarity. This experiment is considered one of the most elegant in modern biology. For additional background on the Meselson-Stahl experiment, see Matthew Meselson and Franklin W. Stahl, “The replication of DNA in Escherichia coli,” Proceedings of the national academy of sciences 44, no. 7 (1958): 671-682. The experiment is described in its immediate historical and scientific context in Horace F. Judson, The Eighth Day of Creation: Makers of the Revolution in Biology (Cold Spring Harbor, NY: CSHL Press, 2013), 289-296.
In addition to his work with Stahl, Meselson also played a role in the discovery of messenger RNA. For an overview of this story, see Matthew Cobb, “Who discovered messenger RNA?” Current Biology 25, 13 (2015): R526-R532. More information about Meselson’s career, including a video about his work, is available here.
The Dr. Matthew Meselson Collection at CSHL is composed of materials accrued by Dr. Matthew Meselson during his doctorate work at the California Institute of Technology from 1953-1957 under Linus Pauling, his tenure as an Assistant Professor at Caltech, his work with Franklin Stahl in 1955-1957 demonstrating self-replication of DNA, and his tenure as a Professor at Harvard University beginning in 1960. The collection consists of correspondence, laboratory files, course notebooks, photographs, reprints, X-ray films, and graphs. The date range is from 1948-2019. Many materials are related to X-ray crystallography, DNA replication, and Drosophila sequencing and heat shock proteins. (This description of the Meselson collection at CSHL is courtesy of our archivists. Detailed information, including the finding aid and our oral history interview with Dr. Meselson, is available here).