The most beautiful experiment in biology

Watson and Crick solved the structure of DNA and everyone lived happily ever after, right? Wrong. That was just the opening argument.

Because once the structure was proposed, everyone needed something new to fight about.

And one of those new topics was how a double stranded DNA helix was copied or 'replicated' to then be passed on to the next generation.

There were three theories for how this might work:

Conservative - A completely new copy of DNA is made that contains no pieces from the parental molecules.

Dispersive - Pieces of the parental molecule are copied and interspersed with fragments of the daughter molecules so the replicated copy is a mishmash of old and new.

Semi-conservative - One strand of a parent molecule serves as a template for creating the daughter strand so one old strand and one new strand end up in the new helix.

Watson and Crick thought the semi-conservative model was the simplest and made the most sense.

But Max Delbrück thought that was impossible because it would require the helix to totally unwind.

He believed that random copying of parent fragments was more likely so he was the champion of the dispersive model.

While the heavyweights were arguing about their theories, Matthew Meselson and Franklin Stahl, two recently minted PhDs, decided to do some actual work.

So, in 1954, they designed a series of experiments to use density gradient ultracentrifugation to settle this latest quarrel.

Now, the method they used might sound complicated but really all they did was extract DNA and spin it really really hard for a very long time - like, 45,000 rpm hard and for 20 hours.

But centrifuging the DNA was only half of the solution, they needed to figure out a way to make ‘old’ DNA strands heavy and ‘new’ ones light.

After a bit of trial and error, they settled on growing bacteria in the presence of a heavy isotope of Nitrogen, N15 and then switching the growth media to regular N14 to see what happened.

If DNA replication was semi-conservative, and not dispersive (random), they hypothesized they would see very sharp bands after centrifugation as the lighter new strands mixed with the old heavy ones.

If there was no banding, and more of a smear, they’d know replication was dispersive.

The results of this experiment are displayed in the figure above and are exactly what would be expected if DNA replicated semi-conservatively.

In Gen 0, everything is heavy, in Gen 1, the helix has one heavy and one light strand, in Gen 2, 50% of the helices are light and 50% are a mix, and by Gen 4, the majority of the DNA helices are composed of light strands.

This simple yet elegant experiment was all it took to convince Max Delbrück that he was wrong and it proved that DNA replication was semi-conservative.