2.2 Semi-Conservative DNA Replication: Meselson and Stahl Citation

This structure has novel features which are of considerable biological interest . . . It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material.
—Watson & Crick (1953)

Perhaps the most significant aspect of Watson and Crick's discovery of DNA structure was not that it provided scientists with a three-dimensional model of this molecule, but rather that this structure seemed to reveal the way in which DNA was replicated. As noted in their 1953 paper, Watson and Crick strongly suspected that the specific base pairings within the DNA double helix existed in order to ensure a controlled system of DNA replication. However, it took several years of subsequent study, including a classic 1958 experiment by American geneticists Matthew Meselson and Franklin Stahl, before the exact relationship between DNA structure and replication was understood.

Three Proposed Models for DNA Replication

Replication is the process by which a cell copies its DNA prior to division. In humans, for example, each parent cell must copy its entire six billion base pairs of DNA before undergoing mitosis. The molecular details of DNA replication are described elsewhere, and they were not known until some time after Watson and Crick's discovery. In fact, before such details could be determined, scientists were faced with a more fundamental research concern. Specifically, they wanted to know the overall nature of the process by which DNA replication occurs.

Defining the Models

Figure 1

Figure Detail

As previously mentioned, Watson and Crick themselves had specific ideas about DNA replication, and these ideas were based on the structure of the DNA molecule. In particular, the duo hypothesized that replication occurs in a "semiconservative" fashion. According to the semiconservative replication model, which is illustrated in Figure 1, the two original DNA strands (i.e., the two complementary halves of the double helix) separate during replication; each strand then serves as a template for a new DNA strand, which means that each newly synthesized double helix is a combination of one old (or original) and one new DNA strand. Conceptually, semiconservative replication made sense in light of the double helix structural model of DNA, in particular its complementary nature and the fact that adenine always pairs with thymine and cytosine always pairs with guanine. Looking at this model, it is easy to imagine that during replication, each strand serves as a template for the synthesis of a new strand, with complementary bases being added in the order indicated.

Semiconservative replication was not the only model of DNA replication proposed during the mid-1950s, however. In fact, two other prominent hypotheses were put also forth: conservative replication and dispersive replication. According to the conservative replication model, the entire original DNA double helix serves as a template for a new double helix, such that each round of cell division produces one daughter cell with a completely new DNA double helix and another daughter cell with a completely intact old (or original) DNA double helix. On the other hand, in the dispersive replication model, the original DNA double helix breaks apart into fragments, and each fragment then serves as a template for a new DNA fragment. As a result, every cell division produces two cells with varying amounts of old and new DNA (Figure 1).

Making Predictions Based on the Models

When these three models were first proposed, scientists had few clues about what might be occurring at the molecular level during DNA replication. Fortunately, the models yielded different predictions about the distribution of old versus new DNA in newly divided cells, no matter what the underlying molecular mechanisms. These predictions were as follows:

According to the semiconservative model, after one round of replication, every new DNA double helix would be a hybrid that consisted of one strand of old DNA bound to one strand of newly synthesized DNA. Then, during the second round of replication, the hybrids would separate, and each strand would pair with a newly synthesized strand. Afterward, only half of the new DNA double helices would be hybrids; the other half would be completely new. Every subsequent round of replication therefore would result in fewer hybrids and more completely new double helices.
According to the conservative model, after one round of replication, half of the new DNA double helices would be composed of completely old, or original, DNA, and the other half would be completely new. Then, during the second round of replication, each double helix would be copied in its entirety. Afterward, one-quarter of the double helices would be completely old, and three-quarters would be completely new. Thus, each subsequent round of replication would result in a greater proportion of completely new DNA double helices, while the number of completely original DNA double helices would remain constant.
According to the dispersive model, every round of replication would result in hybrids, or DNA double helices that are part original DNA and part new DNA. Each subsequent round of replication would then produce double helices with greater amounts of new DNA.