MINING FOR RNA: James Ferris's group at Rensselaer re-creates how nucleotides might have joined on ancient mineral surfaces.
Yet the central role of RNA at life's 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. Orgel-and, independently, Francis Crick at the University of California, San Diego, and Carl Woese at the University of Illinois in Chicago-suggested a role for RNA in the origin of life in the late 1960s.
LOCALIZED ACTIVITY: UC-Santa Cruz's Harry Noller identified one part of the rRNA that participates in peptide bond formation.
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.
The idea of chemicals brewing life is not new. Charles Darwin's private letters envisioned life percolating "in some warm little 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 material-amino acids, purines, pyrimidines, sugars-just 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."
BREWING AMINO ACIDS: An experiment by UC-San Diego's Stanley Miller inspired many variations on the prebiotic synthesis theme.
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 Harvard's 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).
SURPRISE IN GREENLAND: Scripps oceanographer Gustaf Arrhenius and graduate student Stephen Mojzsis discovered the oldest chemical evidence of life.
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.
| The International Society for the Study of the Origin of Life|
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The RNA Society
The Web site http://www.panspermia.org includes a meticulously referenced history of the development of the RNA world hypothesis.
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.
Ferris's 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.
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 Laura Landweber. "Ultimately, this will make the world of possible primordial enzymes accessible even when the molecules are no longer present in modern species."
VIRAL ROLE: New York Hospital-Cornell Medical Center's Hugh Robertson hypothesizes that hepatitis delta virus "captured" an mRNA.
Streamlined RNA viruses may be remnants of an RNA world. "Modern mRNA splicing could be descended from 'captured mosaics' 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.
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?"
PRECURSORS OF LIFE: Several types of molecules may have preceded RNA, says the Salk Institute's Leslie Orgel.
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 shouldn't be restricted to today's biochemistry.
Short of inventing a time machine, can experiments really glimpse an RNA world-or a pre-RNA world? Contends Noller: "I don't see why not. It is impossible to rule out new methods that can tell us things that seem unimaginable today."
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.