By Sean Henahan, Access Excellence

LA JOLLA, CA Two recent studies provide additional support for the presence of RNA as an essential ingredient in the primordial soup of pre-biotic Earth.

The discovery of ribozymes in the 1980's led to the "RNA world" hypothesis. In the RNA world (a term coined by Nobel laureate Walter Gilbert), RNA handled the tasks now managed by DNA and proteins- storing genetic information and catalyzing biochemical reactions. One of the limitations of this idea has been the lack of a plausible route to the creation of two base chemicals that make up genetic material--cytosine and uracil (which occurs in RNA only). This led to the suggestion that alternative bases might have been used as raw material for the first genetic material.

Researchers at UCSD now report they have managed to recreate certain conditions thought to exist on primitive Earth about 4 billion years ago, conditions that would have led to reactions resulting in cytosine and uracil. The chemical route employed was the reaction of a cyanoacetaldehyde--a compound that would have been created by lightning on the primitive Earth--and a concentrated urea solution, such as might have been found in an evaporating lagoon or in pools on drying beaches. When the chemicals were heated, the reaction created high yields of cytosine, from which uracil could then be formed by a simple reaction with water called hydrolysis.

"With this experiment, you don't have to scurry around to look for alternatives to these bases in the first genetic material, if you use the right conditions, " said Stanley Miller, professor of chemistry and biochemistry at UCSD. "The trick is these things were done in lagoons and sea shores rather than in the open ocean. A lot more of this prebiotic chemistry occurred under drying conditions than in very dilute conditions."

Dr. Miller is best known for his experiment conducted at the University of Chicago in 1953, where he and colleagues exposed a flask containing water, methane, ammonia and hydrogen to an electric current. The reaction yielded simple amino acids, suggesting that life on Earth could have been formed by lightning bolts catalyzing the synthesis of chemicals in the ancient atmosphere. Since that time, Dr. Miller has conducted a series of experiments simulating conditions in the primordial ooze. (See related articles in What's News and About Biotechsearch: ribozymes)

"This latest study confirms that the first genetic material may well have been closer to RNA than previously thought," said Dr. Miller.

In another report, researchers at the Whitehead Institute for Biomedical Research and the Massachusetts General Hospital announced work suggesting that complex ribozymes could have formed in a single chemical step rather than evolving over a long period of time.

Seven classes of ribozymes (catalytic molecules made of ribonucleic acid which promote chemical reactions) are known to exist in nature. The Cambridge team and others have used in vitro selection methods to isolate new classes of ribozymes from random RNA sequences. This work has yielded seven families of RNA ligases, which are divided into three classes on the basis of secondary structure and regiospecificity of ligation. Two of these three classes of ribozymes have now been engineered to act as true enzymes, catalyzing the multiple-turnover transformation of substrates into products.

The most complex of these ribozymes has a minimal catalytic domain of 93 nucleotides. An optimized version of this ribozyme shows considerably greater catalytic potential than most natural RNA catalysts, and approaches that of comparable protein enzymes.

"The fact that such a large and complex ligase emerged from a very limited sampling of sequences space implies the existence of a large number of distinct RNA structures of equivalent complexity and activity.," the researchers note.

"We're trying to understand how life arose on earth. The experiments provide a little more evidence that helps us understand the origin of life. This research shows we can get fairly complex enzymes more easily than we thought,'' said Jack Szostak, a molecular biologist at the Massachusetts General Hospital.

The UCSD research appeared in the June 29 issue of the journal Nature. The Cambridge research appeared in Science, 7/21/95, Vol. 269.

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