Molecular Evolution

In cells, replication is controlled by protein catalysts called enzymes. However, since proteins are thought not to have been present on early Earth, how could replication and its related reactions been catalyzed? A key discovery, which has affected how molecular biologists and biochemists view RNA, is that it can also act as a catalyst. In the early 1980s Thomas Cech and Sidney Altman independently discovered RNA (that is, non-protein-based) catalysts in a variety of cell types, whereas scientists had previously thought that only proteins have this power. The concept that RNA could both store information and accelerate biochemical processes made it a much more likely candidate for catalyzing reactions in early life.

The catalytic RNAs (known as ribozymes) found in nature today mainly promote reactions that involve removing certain sequences from an RNA chain before it can be used in protein formation. However, a variety of exotic tools in the molecular biologists' arsenal have now allowed the creation of new ribozymes by in vitro evolution (evolution in a test tube), a method developed by Jack Szostak. He and his associate, David Bartel, showed in 1993 that a novel ribozyme with the ability to link together two RNA chains could be evolved in the laboratory through successive rounds of selection and amplification (creating many copies of the most effective sequence from the previous round). After eight rounds, the best catalyst was faster by a factor of three million, compared to the uncatalyzed reaction.

Bartel has applied this strategy toward the development of the first RNA that catalyzes replication: it binds a smaller RNA template, which then creates a copy that is up to 14 units long. When a set of these replicated products was analyzed, the average accuracy for incorporation of the correct base was 96.7 percent (lowest accuracy was achieved for adenine, greatest for guanine). Although the ribozyme itself was 189 units long and thus represents a highly complex structure that would probably not have formed spontaneously in the early ocean, the experiment demonstrates that RNA can promote the critical step of "peeling off" the copy to allow another cycle of product formation. Such evolutionary exercises thus provide a powerful method for exploring the relationship between ribozyme sequence and the catalytic activity.