RNA and the Origin of Life

The discovery of the role of DNA in heredity launched a debate among biologists as to whether life had its molecular beginnings in protein, the original candidate, or in DNA. DNA was a likely choice because it is the repository of the genetic information and provides the template for its own precise replication: proteins have neither of these qualities. Proponents of proteins, however, argued that virtually all of the chemical reactions of the cell depend on the catalytic activities of proteins. Even the so called self-replicating properties of DNA are actually protein-dependent.

An important clue toward the resolution of this "chicken-and-egg" dilemma came from T. C. Cech and his coworkers at the University of Colorado, Boulder. They were studying the excision of introns and the splicing together of exons. This process must be carried out with exquisite precision; a mistake of one nucleotide could render the entire molecule nonfunctional. By coincidence, the biological system the investigators were using was the unicellular protist Tetrahymena. In order to isolate the catalysts required for the reaction, Cech set up two cell-free systems. One contained not only an RNA molecule from which an intron was to be excised but also proteins that were potential catalysts; the other system, the control, was protein-free. The intron was neatly excised in the first system as expected, but to everyone's surprise, the excision and splicing process also took place in the control. It was subsequently shown that the intron itself—a 400 nucleotide sequence of RNA—has an enzyme-like catalytic activity that carries out the excision and splicing. This sequence folds up to form a complex surface that functions like an enzyme. Although RNA catalysts are not common, other examples have since been found both in other types of reactions and in exon-splicing in other types of cells. Cech called these catalytic RNA molecules ribozymes.

This discovery that RNA can act as a catalyst makes it easier to imagine how life has its beginnings. The discovery that RNA molecules can act as catalysts provides a possible solution to a long-standing dilemma: DNA encodes the genetic information to make proteins, but replication and transcription require proteins so which came first in the evolution of life?

According to Bruce M. Alberts (author of "The Molecular Biology of the Cell"), "One suspects that a crucial early event was the evolution of an RNA molecule that could catalyze its own replication." These molecules then diversified into a collection of catalysts that could, for example, assemble ribonucleotides in RNA synthesis or accumulate lipid-like molecules to form the first cell membranes. Gradually, other RNAs evolved and assembled the first proteins, which gradually took over the enzymatic functions because they were better catalysts. In the third step, DNA appeared on the scene, and its more stable double-stranded structure became the ultimate repository of the genetic information. So, the catalytic intron can be regarded as a living fossil, a provocative clue to the events of almost 4 billion years ago.

Is there evidence that RNA can catalyze the synthesis of proteins? Yes, the ribosome functions as a ribozyme. Ribosomes are large aggregates contains 3 (4 in eukaryotes) rRNA molecues and many protein molecules. The 3-D structure of the large (50S) subunit of a bacterial ribosome was published in August 2000. It clearly shows the formation of the peptide bond that links each amino acid to the growing polypeptide chain is catalyzed by the 23S RNA molecule in the large subunit. The 31 proteins in the subunit probably provide the support needed to maintain the 3-D structure of the RNA.

The ability of ribozymes to recognize and cut specific RNA molecules makes them exciting candidates for human therapy. Already, a synthetic ribozyme that destroys the mRNA encoding a receptor for vascular endothelial growth factor (VEGF) is in clinical trials. VEGF is a major stimulant of angiogenesis, and blocking its action many help starve cancers of their blood supply.