Before there was life, there were chemicals. The idea that ribonucleic acid (RNA), because of its catalytic capability and multiple roles in protein synthesis, was the chemical that led directly to life is termed the RNA world hypothesis. Although the phrase "RNA world" is generally attributed to Walter Gilbert, Harvard Universityís Carl M. Loeb University Professor, in a short 1986 paper, the idea of RNAís importance at the beginning of life was discussed two decades earlier.
The RNA world hypothesis has fueled diverse research approaches, drawing from geology, biochemistry, and evolutionary biology. RNA world studies have been strong and steady for a decade. Researchers are re-creating early Earth conditions, discovering new RNA activities, and uncovering clues to life in the most ancient rocks.
Yet the central role of RNA at lifeís debut is hardly settled. "The world is divided into those who say it was RNA and those who say no because it is hard to make RNA nucleotides and conditions on the prebiotic Earth were not favorable for that," says Leslie Orgel, senior fellow and research professor at the Salk Institute for Biological Studies in San Diego. Orgelñand, independently, Francis Crick at the University of California, San Diego, and Carl Woese at the University of Illinois in Chicagoñsuggested a role for RNA in the origin of life in the late 1960s.
About 20 groups from different countries investigate the RNA world hypothesis, according to James Ferris, a professor of chemistry at Rensselaer Polytechnic Institute in Troy, N.Y. "RNA-world researchers are a subset of the 400 or so people who attend the meeting of the International Society for the Study of the Origin of Life every three years." A hub of activity is in Southern California, where the NASA Specialized Center of Research and Training/Exobiology La Jolla Consortium (NSCORT) funds six major laboratories.
Interest in the RNA world extends far beyond these 20 groups, however, because pondering the very nature of life is what draws many people to life science. When Gerald Joyce, a professor in the departments of chemistry and molecular biology at the Scripps Research Institute in La Jolla, Calif., spoke about the RNA world at the 36th American Society for Cell Biology Annual Meeting in December 1996 in San Francisco, 2,000 people attended! Graduate schools offer courses on the RNA world, and the field has spawned a widely applauded book, The RNA World, edited by Raymond F. Gesteland and John F. Atkins and published in 1993 by Cold Spring Harbor Laboratory Press on Long Island, N.Y.
Evolution Of An Idea
The idea of chemicals brewing life is not new. Charles Darwinís private letters envisioned life percolating "in some warm lime pond, with all sorts of ammonia, and phosphoric salts, light, heat, electricity, etc. present," according to Orgel (L.E. Orgel, Scientific American, 274:77-82, October 1994). Several researchers proposed prebiotic simulations. In 1953, Stanley Miller, a graduate student in the laboratory of University of Chicago chemistry professor Harold Urey, added a spark to a mixture of methane, ammonia, water, and hydrogen gases in a glass bulb, and after a week brewed amino acids seen in organisms (S.L. Miller, Science, 117:528-31, 1953).
The "Miller experiment" inspired many variations on the prebiotic synthesis theme, using different reactants and producing various combinations of amino acids and nucleotides. Miller, now a professor of chemistry at the University of California, San Diego, says such experiments are easy. "Biological materialñamino acids, purines, pyrimidines, sugarsñjust fall out. This is telling us something. The goal is to try to figure out what would happen under a certain set of conditions, see what you get, and hope it could lead to the first genetic material."
Soon after Miller brewed his amino acid primordial soup, attention turned to nucleic acids. The debate over whether proteins or nucleic acids led to life raised a chicken-and-egg paradox. "The problem was that it takes DNA to specify protein," explains Joyce. "This had been a worry since the discovery that DNA encodes RNA, which encodes protein." As RNA emerged as both a conveyor of genetic information and the nuts and bolts of the protein-synthetic machinery, many investigators began to focus on it as critical to lifeís origin. The discovery of RNA-based enzymes, or ribozymes, settled the chicken-and-egg paradox.
According to Ferris, "what really initiated the current interest in the RNA world" was the work of Tom Cech at the University of Colorado, who found self-splicing RNA in Tetrahymena, a protozoan (T.R. Cech et al, Cell, 27:487-96, 1981). In addition, Sidney Altman at Yale University did landmark studies on RNase P in E. coli, which catalyzes cutting of phosphodiester bonds in transfer RNA. Altman "showed that RNA was all that was needed for catalysis," Ferris notes (C. Guerrier-Takada, S. Altman, Science, 223:285-9, 1984). This was the work for which Cech and Altman won the 1989 Nobel Prize in chemistry. The discovery of ribozymes prompted Harvardís Gilbert to state in less than a page in Nature the RNA world hypothesis: "One can contemplate an RNA world, containing only RNA molecules that serve to catalyze the synthesis of themselves" (W. Gilbert, Nature, 319:618, 1986).
Experimental approaches today probe what might have happened on an RNA world. "The way to approach this question is to model experiments in the laboratory to try to find processes that could have, in nature, spontaneously given rise to fundamental information-carrying, self-reproducing molecules, particularly RNA or some structurally similar precursor," notes Gustaf Arrhenius, a professor of oceanography at the Scripps Institution of Oceanography in La Jolla, Calif. "It is an intricate jigsaw puzzle, and we have no idea yet how easy or difficult it was to make fully functional RNA."
Clues In The Earth
Arrhenius and graduate student Stephen Mojzsis are placing the RNA world into a temporal perspective. They recently discovered the oldest chemical evidence of life in sedimentary rocks from Greenland. The rocks are estimated to be more than 3.85 billion years old. Carbon in these rocks had an isotope profile seen only in remains of organisms (S.J. Mojzsis et al., Nature, 384:51-9, 1996). "The evidence of the carbon signatures is crucial in arguing that life on Earth was present before 3.85 billion years ago," maintains Mojzsis. "Furthermore, the carbonaceous matter was found in intimate association with the phosphate mineral apatite, a common biologically formed substance." Phosphates exist in cell membranes, enzymes, genetic material, and biological energy molecules.
Yet even this most ancient evidence indicates life far more complex than the molecular entities of an RNA world. "The chemofossil evidence in rocks at least 3.85 billion years old indicates that these organisms had already developed the enzyme mechanisms, used by present-day life, for converting inorganic chemicals to living matter," explains Arrhenius. "These enzymes produce the uniquely strong carbon isotope fractionation characteristic of todayís microorganisms."
Those first organisms might have formed from molecules held in place by, and polymerized on, minerals. But these places would have to have been protected, because conditions on the early Earth were too harsh to have nurtured the rather unstable RNA, many researchers say. Norman Pace, a professor of plant and microbial biology at the University of California, Berkeley, describes the Earth then as a hellhole of 500∞C temperatures and high pressures (N. Pace, Cell, 65:531-3, 1991): "RNA is fragile. It would not have persisted under the conditions on the early Earth unless it was coated on something." Clays and other minerals may have provided such surfaces, while shielding nucleic acids from the water that would tear them apart as they were made. A catalyst would have been necessary, too.
Ferrisís research group re-creates how nucleotides might have joined on long-ago surfaces. They have found that an adenine derivative and certain amino acids form polymers up to 55 units long on particular clays or minerals (J.P. Ferris et al., Nature, 381:59-61, 1996). "In my model, the first life was RNA bound to a mineral surface. The RNA would eventually have to catalyze [its own replication] better than the mineral can, then start construction of phospholipids and other chemicals to isolate it, in a bag, from the environment," Ferris says.
Clues In RNA
The RNA world hypothesis is based on what we know of RNA function today. Learning more about what RNA can do suggests what the molecule might have done at the dawn of life. Harry Noller, the Robert L. Sinsheimer Professor of Molecular Biology at the University of California, Santa Cruz, and colleagues focus on ribosomes, the structures on which amino acids link to form polypeptides. Ribosomes consist of RNA and proteins. Because enzymes were traditionally known to be proteins, the ability to catalyze bond formation between amino acids was attributed to ribosomal proteins. Noller and his group have identified the catalytic role of ribosomal RNA (rRNA) in protein synthesis by removing ribosomal proteins and demonstrating that enzymatic activity remains (R. Samaha et al., Nature, 377:309-12, 1995). And they have localized that activity. "We have recently identified one part of the rRNA that participates in peptide bond formation," he explains. "We believe that there are several others, which come together in three dimensions to form the active site."
Laura Landweber, an assistant professor of ecology and evolutionary biology at Princeton University, studies another RNA function, called RNA editing. This is the addition or deletion of uridines from mitochondrial genes in protozoa. She sees RNA editing as a "molecular fossil," reflecting a time when RNA pieces were spliced and edited, eventually giving rise to a genome (L.F. Landweber, W. Gilbert, Proceedings of the National Academy of Sciences, 91:918-21, 1994). "RNA editing could have distinguished functional from informational RNA molecules, controlled or modulated their activity, or tagged specific ones for certain functions, such as replication or metabolism, in an RNA-based 'organism,'" she says.
An experimental approach, called in vitro evolution, discovers new catalytic roles for RNA by screening and selecting RNAs with specific activities from an enormous number of randomly generated RNA molecules of differing sequences. Charles Wilson, an assistant professor of biology at UC-Santa Cruz, and Jack Szostak, a professor of molecular biology at Massachusetts General Hospital, searched 500 trillion RNAs for those that bind a biotin derivative, collected by affinity chromatography in which streptavidin immobilized in agarose binds biotin. They discovered that RNA that binds biotin can catalyze formation of bonds between carbon and nitrogen, an activity that would have been essential to string together amino acids to form proteins on a primordial Earth. "The ability to isolate new ribozymes from random sequences has fueled a new excitement about the possibility of uncovering early pathways of RNA evolution," says Wilson. "Ultimately, this will make the world of possible primordial enzymes accessible even when the molecules are no longer present in modern species."
RNA viruses are another source of modern RNA that may hold clues to an RNA world. Consider hepatitis delta virus (HDV), which infects people who already have hepatitis B, with a 20 percent fatality rate. HDV is an RNA molecule that can replicate and therefore infect; it also encodes a protein antigen. This RNA wraps itself in the envelope from hepatitis B. Hugh Robertson, a professor of biochemistry at New York Hospital-Cornell Medical Center in New York, hypothesizes that HDV is a viroid (an infectious RNA) that somehow "captured" an mRNA, which encodes protein (H. Robertson, Science, 274:66-9, 1996).
Streamlined RNA viruses may be remnants of an RNA world. "Modern mRNA splicing could be descended from ëcaptured mosaicsí of viroid-like and protein-coding domains, which arose originally in the RNA world by a process similar to that which led to HDV, and which were subsequently copied into DNA," Robertson hypothesizes.
A Pre-RNA World
Perhaps an informational polymer tougher than RNA led to life. "In my opinion, the first molecule was not RNA, for reasons of stability and synthesis," states Miller. "There was a time before the RNA world, the pre-RNA world, with a different molecule, with a different backbone, and maybe different bases. But what is the other molecule?"
Orgel takes the thought a step further: "If there had to be something before RNA, was there just one, or several types of molecules? One can think of one genetic system inventing RNA, and another inventing another inventing another, and so on."
A strong candidate for a pre-RNA world informational molecule is a peptide nucleic acid, or PNA. It has bases bound to a peptide-like backbone, in contrast to the sugar-phosphate backbone of RNA. PNA is synthetic and not known to exist naturally, but it binds tenaciously to DNA. Miller and Orgel note that they do not know whether PNA was actually the molecule from which life sprang, but maintain its existence suggests that thinking on the origin of life shouldnít be restricted to todayís biochemistry.
Short of inventing a time machine, can experiments really glimpse an RNA worldñor a pre-RNA world? Contends Noller: "I donít see why not. It is impossible to rule out new methods that can tell us things that seem unimaginable today."
By Ricki Lewis
Ricki Lewis, a freelance science writer based in Scotia, N.Y., is the author of several biology textbooks. She is online at firstname.lastname@example.org.
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