After Watson and Crick published their structure of DNA in Nature in 1953, the race was on to empirically demonstrate its correctness because, in fact, Watson and Crick's model had precious little going for it other than the fact that it was so damned pretty.
The beauty of the Watson-Crick model is that the structure implies that information can be coded in the sequence of bases and this sequence can be replicated by splitting the double helix in two and constructing new double helixes from the two single strands. But how to prove this?
Enter Caltech grad student Matt Meselson and postdoc Frank Stahl. The two met in a physiology course at the MBL in Wood's Hole: "I partied my way through that course," Stahl confesses. "During the partying, I met Meselson."
Meselson and Stahl decided they could determine how DNA replicated when all the big shots, such as the great Delbruck (see Delbruck, PNAS, 1954), had failed. They spent a couple of years futzing around with phages before hitting upon the idea of using E. coli and heavy nitrogen. 15N contains an extra neutron and molecules made with it would be heavier than molecules containing 14N. So Meselson and Stahl grew E. coli in 15N for many generations, resulting in cells with much heavier than normal DNA. This DNA was extracted, combined with DNA from normal E. coli, and ultracentrifuged in a cesium chloride solution. The photos of the ultracentrifuged DNA showed that the lighter DNA formed one band and the heavier DNA formed another. So far, so good.
Now the clincher. The cells grown in 15N were now transferred to regular 14N media and allowed to grow for one generation. This DNA was then extracted and ultracentrifuged. This DNA showed a band intermediate to that of the heavy DNA and the light DNA. Why? Because the original heavy DNA split in two and a new light DNA chain was constructed to match the parental heavy DNA strain. Semi-conservative replication!
“Stahl credits the beauty and success of their paper to two things. First, the "delightfully clean data" were serendipitous. The clean data peaks they observed resulted from the DNA fragmenting during handling; unfragmented DNA would not have separated as nicely. Stahl likens pipetting DNA to "throwing spaghetti over