Contact: Robert Irion (408/459-2495)
"RNA WORLD" SCENARIO OF THE ORIGIN OF LIFE GAINS FURTHER SUPPORT
* This press release is EMBARGOED until 6 p.m. EDT Wednesday, April 26, 1995. The study will appear in the April 27 issue of the journal Nature.
SANTA CRUZ, CA--The theory that RNA was the central molecule in the origin of life has received a major boost from a clever test-tube experiment, in which researchers demonstrated that RNA can execute a type of chemical reaction that is basic to all living cells.
Starting with 500 trillion bits of random RNA, molecular biologists Charles Wilson and Jack Szostak of Harvard University's Massachusetts General Hospital devised a way to find the few RNAs that could stick most readily to another substance. Then, in a rapid- fire simulation of evolution on the early earth, they mutated the RNAs to create a special RNA enzyme--a "ribozyme." The ribozyme was able to forge a bond between atoms of carbon and nitrogen.
That reaction reveals a far broader set of chemical skills than scientists previously had credited to RNA, says Wilson, now at the University of California, Santa Cruz.
"All other known ribozymes carry out the same basic reaction: breaking and making bonds in the RNA backbone between phosphorus and oxygen," Wilson says. "Some RNAs cut and paste themselves together, but that involves similar reactions. To test the idea of an RNA world, we needed to look for other reactions beyond this backbone chemistry."
The reaction targeted by Wilson and Szostak, the carbon- bonding process called "alkylation," would have been critical to the success of RNA as life arose. "This basic reaction comes up in all types of biological situations," Wilson says. "Our results suggest that RNA could have reacted with other molecules that didn't look like RNA. That's the first step of evolution toward a non-RNA world."
Wilson and Szostak published their work in today's issue (April 27) of the journal Nature. Until last year, Wilson was a postdoctoral researcher in the laboratory of Szostak, a professor in the Department of Molecular Biology at Massachusetts General Hospital. Wilson now is an assistant professor of biology at UC Santa Cruz and is a member of UCSC's Center for the Molecular Biology of RNA.
In today's organisms, nearly all chemical reactions are catalyzed by proteins, powerful enzymes that have evolved to master a bewildering array of tasks. However, proteins cannot carry a cell's genetic information. That deed is the domain of the nucleic acids: double-stranded DNA and its single-stranded relative, RNA. Although DNA is more widely known, scientists have found that RNA is far more complex and versatile.
Modern proteins and nucleic acids need each other to exist and function. However, it is extremely unlikely that these two complex types of molecules evolved together on the young earth. Within the last decade, biologists have turned to RNA as a way out of this chicken-and-egg paradox. In addition to acting as a genetic librarian and stenographer, RNA can mimic proteins by triggering certain reactions. But until now, that class of reactions had seemed limited.
Wilson and Szostak sought to push the edge of the RNA envelope by accelerating the selective pressures that primitive RNA might have faced. Their method, "in vitro evolution," is used in several labs worldwide. In essence, it lets researchers find the fittest chemical needles in an immense haystack of random molecules--the sort of rich mixture that could have set the stage for the first living cells.
Wilson and Szostak have applied for a patent on their method of evolving ribozymes. They started by creating a pool of about 500 trillion RNA molecules, each consisting of 112 of the genetic units that carry RNA's information. The middle 72 units of each molecule were strung together overnight in random patterns by a computerized machine called a nucleic-acid synthesizer. Although it filled just a fraction of one test tube, that broth of RNAs was about 10 million times more complex than the genetic encyclopedia for a human being.
Among those molecules lurked one that was especially adept at latching onto a non-RNA substance. The researchers used a discriminating screen to purge the molecules that couldn't latch on at all, then made billions of copies of those that remained after each screen. Remarkably, it took only seven such steps to isolate the one piece of RNA that formed a tighter fit than the other 500 trillion.
Wilson and Szostak then sought to modify that RNA so it could catalyze the carbon-nitrogen bond with no help from proteins. They randomly changed some of the RNA's genetic units-, so that each one had a 30 percent chance of being different from the corresponding genetic unit in the starting framework. This led to another huge pool of 80 trillion slightly different RNAs. Next, the researchers explored the abilities of these mutated RNAs to stick to the non-RNA substance and to catalyze the carbon-nitrogen alkylation.
Seven more screening steps led to one ribozyme that could turn both tricks most speedily. Finally, Wilson and Szostak improved the efficiency of this molecule 100-fold by mutating it further and subjecting it to another round of screens.
Even so, the RNA enzyme is not nearly as fast as today's natural proteins. "The slowness of this ribozyme might reflect the intrinsic incompetence of RNA to carry out the reactions that proteins do so well," Wilson says. "That may be why the RNA world evolved into a protein world--proteins outcompeted RNA in these functions. But we don't know that our ribozyme is the best one possible. We could optimize it further."
To Wilson and Szostak's surprise, the apparent structure of their final ribozyme looks like that of a well-known RNA molecule in the cells of all living things: the cloverleaf-shaped "transfer RNA." Wilson now is trying to determine why this shape arose in the experiment and how it works. "It's striking to me that we started with an enormous random pool with no bias," he says, "but we ended up with basically the only RNA whose structure we really know."
The research was funded by the National Institutes of Health and Hoechst A. G., a German chemical company. Wilson's postdoctoral appointment was supported by the Jane Coffin Childs Memorial Fund for Medical Research.
Editor's note: You may reach Wilson at (408) 459-5126 or
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