the Meselson-Stahl experiment
/ MESS-el-son STAHL /
How do you actually prove how DNA copies itself, when each molecule is far too small to watch? In 1958 Matthew Meselson and Franklin Stahl found a beautiful trick: make the old DNA slightly heavier than the new DNA, then weigh it. The experiment is so clean it is often called 'the most beautiful experiment in biology.'
They grew E. coli for many generations on a heavy form of nitrogen (15N), so all the DNA bases were built with the heavy isotope and the DNA was uniformly dense. Then they switched the cells to ordinary light nitrogen (14N) and let them divide. New strands now used light nitrogen. By spinning the DNA in a tube of cesium chloride, which forms a density gradient, the DNA settled at a height set by its density. After one round of copying, all the DNA was a single intermediate (hybrid) band — exactly one heavy old strand paired with one light new strand. After a second round, the DNA split into two bands: half hybrid, half fully light.
That pattern matches only semiconservative replication. Conservative copying would have given a heavy band and a light band after the first round (never a single hybrid band), and dispersive copying would have given a band that got progressively lighter but never split cleanly into two. The result settled the question decisively and is a textbook model of how a careful physical measurement can decide between biological hypotheses.
Generation 0: one heavy band. After one division in light nitrogen: one hybrid (intermediate) band. After two divisions: one hybrid band plus one light band, in equal amounts. That progression is the signature of semiconservative copying.
Density-gradient banding distinguishes the three models.
15N is a stable heavy isotope, not radioactive — the experiment separated DNA by weight (density), not by radioactivity, which is why people sometimes confuse it with labelling experiments like Hershey-Chase.