Sep. 17, 1998 For decades, many researchers thought that ribonucleic acid, or RNA, was nothing more than a molecular interpreter that helps translate DNA codes into proteins. But research over the past 15 years, including studies at the Whitehead Institute, has been lending credence to the notion of a so-called "RNA world," an era in early evolution when all life forms were based on RNA.
This view faced a difficulty, however. For RNA-based life to survive, it must have acquired the ability to synthesize its own building blocks, and until now, scientists had not found an RNA molecule with this key characteristic.
In this week's issue of Nature, Drs. David Bartel and Peter Unrau of the Whitehead Institute report that they have found an RNA molecule capable of making a nucleotide building block, providing some of the strongest evidence yet to support the RNA world view. In contemporary metabolism, protein enzymes catalyze this nucleotide-synthesis reaction, which involves the addition of a nucleotide base to a sugar phosphate. For the RNA world scenario to be feasible, scientists had to show that RNA molecules could catalyze this reaction without the help of protein enzymes.
The Bartel lab finding provides this evidence and supports the theory that in early evolution, RNA molecules carried out functions now considered to be the domains of DNA and proteins: like DNA in modern biology, RNA stored the genetic information to reproduce, and like protein, RNA synthesized the molecules needed to reproduce.
These and other findings will ultimately help evolutionary biologists address questions about how life began on earth more than three billion years ago.
Theories about the origins of life have long intrigued scientists and lay people alike. "A fundamental question about the origin of life is what class of molecules gave rise to some of the earliest life forms" says Dr. Bartel.
For years, scientists debated this question, some arguing that RNA molecules were the progenitors and others arguing in favor of proteins. "It was a classic chicken-and-egg argument. RNA has the genetic information necessary to reproduce but needs proteins to catalyze the reaction. Conversely, proteins can catalyze reactions but cannot reproduce without the information supplied by RNA," says Dr. Bartel.
The discovery in 1982 of ribozymes, a class of RNA that catalyze chemical reactions, has bolstered the notion that RNA came before protein, but more challenges lay ahead for evolutionary biologists before they could espouse the RNA world view. For one, there are only seven known ribozymes in nature, nowhere near enough to sustain the range of reactions in an RNA world. Further, compared to protein enzymes, ribozymes seemed slow as catalysts. So scientists set out to make artificial ribozymes that were more versatile and efficient than the natural ones. If they could create such ribozymes in the lab, it would suggest that natural ones could have existed during the RNA era but have become extinct since.
In the past five years, Dr. Bartel and his colleagues have used the method of making trillions of RNA go through test-tube evolution (a technology that selects for the fittest molecules and introduces errors in successive generations of copies much like in real evolution) to gather further evidence in favor of the RNA world view. They have shown that complex ribozymes are more common than previously thought and can be quite efficient. In addition, two years ago, the scientists showed that RNA could synthesize a short piece of RNA using the same strategy used by protein enzymes that make RNA.
Still, doubts remained because scientists had never been able to find a ribozyme that could synthesize the nucleotide building blocks from simpler precursors. Although scientists could propose ways by which the four RNA bases (A, C, G, and U) and the ribose-phosphate sugars could have arisen spontaneously on the early earth, these prebiotic reactions do not seem to be sufficient for linking the base to the sugar phosphate, the critical step to making nucleotides.
In this study, Whitehead scientists took the approach of making 1000 trillion random RNA molecules go through test-tube evolution to find those that could catalyze nucleotide formation. They found three different families of ribozymes that synthesize a nucleotide by linking the base to a sugar phosphate, a reaction similar to those used by proteins in contemporary metabolism.
"These ribozymes make only one nucleotide, and that is not enough. But the fact that they can do this is encouraging, and we plan to try further evolution to see if we can make them better and more efficient," says Dr. Bartel.
"We will never be able to prove the existence of the RNA world because we can't go back in time, but we can examine the basic properties of RNA and see if these are compatible with the RNA world scenario."
This work was supported by a MRC (Canada) postdoctoral fellowship and a grant from the Searle Scholars Program/The Chicago Community Trust.
The title of the Nature paper is "RNA-Catalyzed Nucleotide Synthesis." The authors are: Peter J. Unrau, Postdoctoral Fellow, Whitehead Institute for Biomedical Research, and David P. Bartel, Member Whitehead Institute for Biomedical Research.
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