Could RNA Spell Life?

RNA (ribonucleic acid) has often played the forgotten middle child in biology’s family of macromolecules. The central dogma of biology states that information flows from DNA to RNA to proteins, but RNA often lacks the attention lavished on DNA and proteins. While DNA is the "blueprint" of the cell and proteins do the "work" necessary for the cell to function, RNA is often thought of as just a messenger, but evidence is building which suggests RNA may be much more. The many abilities of RNA have scientists wondering exactly what role it may have played in the origin of life.

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In order for cells to function they must be able to drive chemical reactions that would normally occur at very slow rates. Proteins are responsible for acting as catalysts to push these chemical reactions forward. Proteins with catalytic activity are called enzymes. Every protein has a different structure and it is the physical structure of the protein that confers catalytic activity. DNA on the other hand consistently forms only one structure, the double helix. Although RNA resembles DNA closely in its composition- both are long strings of four different subunits called nucleotides- it is able to produce a variety of structures, much like proteins.

For a long time RNA's role in the cell was unknown. DNA provided the genetic information necessary to build proteins; proteins provided the structural elements and activity of the cell, but how RNA fit into this system was unclear. In 1954 some of the brightest minds in biology, including Watson and Crick, the discoverers of the double helix structure of DNA, formed a society known as the RNA Tie Club. The club contained 20 members, one for each of the subunits used to build proteins. They gathered twice a year to discuss the mystery of this enigmatic macromolecule and don matching ties embroidered with an RNA helix. By 1960 a case had been made for RNA’s role as a messenger in the cell: shuttling between the nucleus, where DNA is stored, and the cytoplasm, where proteins are made.

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During the early 80s it was discovered that RNA could also have catalytic activity, just like a protein. While this interested some scientists, few believed it was important for the normal functioning of a cell. Then, in 2001 scientists were stunned when the crystal structure of the ribosome was published. The ribosome is a critical structure in cells. It is a large complex made of protein and RNA. It had been assumed that proteins provided the catalytic activity of the ribosome, but the crystal structure showed that it was actually the work of RNA. An RNA enzyme, a ribozyme, played a key role in the cell.

This breakthrough discovery is what brought Tracey Lincoln into the RNA arena. “I took a class while I was a junior in college, enzyme kinetics. My professor told the class that if we got through all of the syllabus he’d show us something really cool; so we got through the whole thing. The crystal structure of the ribosome had just been done, and he was like ‘look the catalytic component of the ribosome is a ribozyme’. This was extremely important; something so central to all of biology was an RNA enzyme,”says Lincoln. Lincoln’s professor encouraged her to apply to the Scripps Research Institute in San Diego, where a lot of interesting RNA work was being done. She is currently a graduate student in the Joyce lab, which studies the enzymatic properties of RNA using in vitro evolution, or evolution in the tube.

To make evolution happen in a test tube, researchers break it down into three component processes: mutation, selection and amplification. A pool of molecules can be mutagenized and then presented with a specific challenge or selective pressure. Molecules that rise to this challenge will be amplified and come to dominate the pool. Using this type of experiment researchers can learn exactly what catalytic activity RNA is capable of. “RNA can be catalytic, be it cleavage or joining. RNA can’t do as many reactions as proteins, or as fast as proteins, but it can do a certain number of reactions and its all governed by the sequence and the structure. We don’t really know all the things that RNA can do and we continually ask it do different things,” says Lincoln.

In vitro evolution studies also help researchers determine exactly what components are critical for RNA catalytic activity. A paper published in Nature in 2002, based on work done by the Joyce Lab, showed that ribozymes containing only two of the four nucleotides found in modern RNA could still produce molecules with catalytic activity. Since it is believed that some nucleotides were much rarer than others during the time when life evolved, this type of in vitro evolution experiment helps scientists more clearly understand the way life on earth may have begun.

One theory that has received strong support is the “RNA world hypothesis” which starts with the idea that free-floating nucleotides, the building blocks of RNA, existed in the primordial environment. These nucleotides regularly formed and broke bonds with one another, but some of these bonds would lead to nucleotide chains that had catalytic activity. Chains with catalytic activity would be able to protect their bonds or generate copies of themselves better than chains lacking catalytic activity, giving them an advantage over the other nucleotide chains. These chains would have been the first primitive forms of life.

As RNA research continues to explore the plausibility of theories like the RNA world hypothesis, it is also making researchers look more closely at how they define life. In a review by Dr. Gerald Joyce titled “Forty Years of In Vitro Evolution” he states: “An overarching goal of in vitro RNA evolution research is to develop a system that can evolve in a self-sustained manner….By some definitions this would be the realization of life in the laboratory.”

Lincoln and Joyce have made strides toward achieving this goal. In a paper published in Science Express on January 8th, they created a system in which two RNA enzymes catalyze the synthesis of one another. The ribozymes in this system can generate their products indefinitely. Studying this self-sustained system will offer scientists the chance to view ribozyme activity as it may have existed in the RNA world. This will be the first time in history researchers have had this opportunity. This recent work by Lincoln has generated a buzz in the science world and been featured by the BBC, New Scientist and NPR.

Research has answered many of the original questions scientists once had about RNA. At the same time it has brought to light exciting properties whose full importance may never be completely known. By studying the evolution of RNA researchers will doubtless gain insights into the nature of RNA and the process of evolution itself. Along the way they may answer one the most pervasive questions for humanity: Where did we come from?

Author: Jennifer Rust for MySDsciene

January 21, 2009