Meselson, Stahl, and the Most Beautiful Experiment in Biology

In Chapter 17 of Intermediate Physics for Medicine and Biology, Russ Hobbie and I added a new homework problem to the 5th edition about the famous Hershey-Chase experiment. We had two goals: to demonstrate how scientists use radioisotopes as tracers in biological experiments, and to describe a key experiment in modern biology.

A series of homework problems in Chapter 1 of IPMB describe the physics of the ultracentrifuge. Perhaps Russ and I should add a new homework problem in Chapter 1, to demonstrate how the centrifuge provides crucial information about biological mechanisms, and to describe another famous biological experiment. Here is my try at this new problem.

Problem 24 1/2. Suppose you grow E. coli bacteria in a growth medium containing the rare, heavy but stable isotope of nitrogen, N¹⁵. At some time t = 0 remove some of the E. coli from this medium and place it into another growth medium containing the normal isotope of nitrogen, N¹⁴. Then, at different times place DNA from the E. coli into a density gradient centrifuge (see Problem 23) and measure where along the gradient the DNA settles.

a) Describe qualitatively what you would expect to see at t = 0, before any of the E. coli reproduce.

b) Assume DNA replicates semiconservatively: replication produces two new DNA molecules, each containing two strands: one a strand from the original DNA molecule and another new strand produced from the medium. Describe what you would expect to see at t = t₁, where t₁ is the time required to produce one new generation of E. coli. Describe what you would expect to see at t = 2 t₁. 

c) Repeat part b) assuming DNA replicates conservatively: each replication produces two DNA molecules, one containing the original two strands and the other containing two new strands. 

d) Repeat part b) assuming DNA replicates dispersively: each replication produces two new DNA molecules, both containing a mix of the original and new DNA. 

This experiment was performed by Meselson and Stahl in 1958, and is one of the central experiments underlying modern biology. It demonstrates the semiconservative replication of DNA.

If you want to learn more about the Meselson-Stahl experiment, I suggest reading Chapter 3 of The Eighth Day of Creation: The Makers of the Revolution in Biology, by Horace Freeland Judson. Below I provide an excerpt.

“I first heard of semiconservative replication on New Year’s Day, 1958, in Chicago—and a bright, windy, iron-cold morning it was. Seven of us who had been undergraduates together at the University of Chicago (we had all overlapped Watson’s last year there) were sitting scratchy-eyed over bacon and eggs and coffee when Matthew Meselson, by then a doctoral candidate with Pauling at Cal Tech, took a photograph from his wallet and passed it around the table. The picture showed a stack of gray stripes, with narrow, dark-gray bands across them—some stripes with one band, some with two or three together near the middle. The photo was the main result of an experiment that Menelson had devised with a post doctoral fellow at Cal Tech, Franklin Stahl.

Their paper was not yet published—not yet written. The work it describes is now recognized as displaying the most rare technical skill, while conceptually its confirmation of the way DNA reproduces itself has become, simply, part of the mainstream. In its place towards the end of the history of the elucidation of the structure and function of DNA, Meselson’s and Stahl’s paper possessed an importance and authority like Oswald Avery’s announcement, fourteen years earlier, of the isolation of the transforming principle and its identification as DNA. ‘Classic’ was Watson’s epithet for Meselson’s and Stahl’s paper. Watson’s predecessor as director of the Cold Spring Harbor Laboratory, John Cairns, startled me in conversation when he described Meselson’s central demonstration without qualification as ‘the most beautiful experiment in biology.’“