It is generally believed that there was a time in the early history of life on Earth when RNA served as both the genetic material and the agent of catalytic function.
Gerald Joyce, 1991
In spite of the elaborate detail of Wächtershäuser’s Iron–Sulfur World, most origin experts dismiss the idea of a purely metabolic life-form in favor of a genetics-first scenario. In order to reproduce, even the simplest known cell must pass volumes of information from one generation to the next, and the only known way to store and copy that much information is with a genetic molecule similar to DNA or RNA.
No one has thought more deeply about genetics and the origins of life than Leslie Orgel at the Salk Institute for Biological Studies in San Diego. His classic 1968 paper, “Evolution of the genetic apparatus,” has guided generations of researchers, and he continues to exert a tremendous influence on origin theory and experiment. Orgel states that the central dilemma in understanding a genetic origin of life is the identification of a stable, self-replicating genetic molecule—a polymer that simultaneously carries the information to make copies of itself and also catalyzes that replication. Accordingly, he catalogs four broad approaches to the problem of jump-starting such a genetic organism.
One possibility is the emergence of a self-replicating peptide of the kind made by Reza Ghadiri’s group at Scripps, or perhaps a protenoid as championed by Sidney Fox. The idea that proteins emerged first and then “invented” DNA holds some appeal, because amino acids, the constituents of proteins, are thought to have been available in the prebiotic environment. The problem is that the random prebiotic assembly
of amino acids would have been a messy business, as Fox’s critics were quick to point out. Cells have learned how to form neat, chainlike polymers—the proteins essential to life. But left to their own devices, amino acids link together in irregular, undisciplined clusters—hardly the stuff of genetics.
The second of Orgel’s possibilities, the simultaneous evolution of proteins and DNA, seems even less likely, because it requires the emergence of not one but two improbable macromolecules.
Graham Cairns-Smith’s Clay World scenario provides an intriguing third option, with genetic-like sequences of elements replicating and acting as templates for organic assembly. So far, however, the Clay World scenario is totally unsupported by experimental evidence.
The fourth and favored genetics-origin model of Orgel and many followers is based on a nucleic-acid molecule such as RNA—a single-stranded polymer that acts both as a carrier of information and as a catalyst that promotes self-replication. Orgel proposed this model in 1968, long before any experimental evidence supported such a notion. “I must confess to a strong, longstanding bias in favor of [this] explanation,” he remarked recently. “It is, at the very least, the model that can be studied most easily in the laboratory.”
How to choose? When evaluating various origin-of-life models, scientists aren’t restricted to chemical experiments alone. The metabolism-first models of Wächtershäuser, de Duve, and others are equally influenced by top-down studies of molecular phylogeny, which point to deeply embedded, primordial biochemical pathways. The principle of continuity demands an unbroken path from ancient geochemisty to modern biochemistry. Hence, the citric acid cycle that lies at the heart of all modern metabolism becomes a prime target for studies of protometabolism.
In like fashion, top-down studies of molecular genetics have zeroed in on RNA as the essential core molecule of ancient genetics.
Few events have electrified the origin-of-life community as much as the early 1980s discovery of RNA ribozymes—strands of RNA that not only carry genetic information, but also act as catalysts. Sidney Altman of Yale and Thomas Cech of the University of Colorado independently demonstrated that a particular segment of RNA can accelerate key bio-
chemical reactions. This startling finding, which won Altman and Cech the Nobel Prize in 1989, inspired a new vision of life’s origin.
Modern life relies on two complexly interrelated molecules: DNA, which carries information, and proteins, which perform chemical functions. This interdependence leads to a kind of chicken-and-egg dilemma: Proteins make and maintain DNA, but DNA carries the instructions to make proteins. Which came first? RNA, it turns out, has the potential to do both jobs
The RNA World theory quickly emerged following the discovery of ribozymes. It champions the central role of genetic material in the dual tasks of catalyst and information transfer. Over the years, “RNA World” has come to mean different things to different people, but three precepts are common to all versions of the theory: (1) Once upon a time, RNA rather than DNA stored genetic information; (2) ancient RNA replication followed the same rules as modern DNA replication by matching pairs of bases: A-U (the pyrimidine uracil, whose DNA equivalent is thymine) and C-G; and (3) ancient RNA played the same catalytic roles as modern protein enzymes. In this scenario, the first life-form was simply a self-replicating strand of RNA, perhaps enclosed in a protective lipid membrane. According to most versions of this hypothesis, modern metabolism emerged later, as a means to make RNA replication more efficient.
Two factors may have contributed to the speed with which the RNA World idea caught on. For one thing, a generation after the Miller–Urey experiment, there were still few solid clues about how to make the transition from the prebiotic soup to cellular life. The origin-of-life community was poised to try something new, and RNA provided a compelling original angle, rich in experimental possibilities. In addition, evidence of the dual role of RNA, as both catalyst and carrier, proved seductive to the new generation of biologists, who were born and raised in the age of molecular genetics. To many researchers, life and genetics are synonymous, so the RNA World idea resonates deeply.
The more that biologists learn about RNA, the more remarkably versatile it seems. One big surprise came from the study of ribosomes, lumpy cellular structures that help to assemble proteins. Ribosomes consist of a complex intergrowth of proteins and several RNA strands. Many biologists assumed that the proteins play their usual active role as the enzymes that do the actual assembly work, while RNA merely holds the ribosomes together. However, recent studies prove just the
opposite—that RNA mediates the critical step of linking up the protein’s constituent amino acids. In essence, RNA does the heavy lifting in protein assembly—a discovery that strongly reinforces RNA’s presumed ancient role in biochemistry.
RNA’s probable antiquity is underscored by a growing list of other biochemical studies. For example, RNA nucleotides play key structural roles in a variety of essential biological catalysts called coenzymes. These versatile catalysts promote vital reactions at the very heart of the citric acid cycle (the difficult synthesis of citrate from oxaloacetate, for instance). Coenzymes also mediate the manufacture of lipids and other essential biomolecules. And recently, scientists at Yale discovered “riboswitches”—remarkable segments of RNA that change shape when they bind to specific molecules in the cell. These chemical sensors then regulate the cell’s chemistry by turning genes on and off.
The inevitable conclusion: RNA is a very ancient molecule that seems to “do it all.”
Today, every origin-of-life meeting features sessions dedicated to RNA World studies. A thousand articles amplify the idea, and hundreds of researchers have pursued variations on the theme. There can be little doubt that the emergence of RNA represents a crucial step in life’s origin. However, decades of frustrating chemical experiments have demonstrated that the RNA World could not possibly have emerged fully formed from the primordial soup. There must have been some critical transition stage that bridged the prebiotic milieu and the RNA World.
I am persuaded by those who argue that a self-replicating metabolic system must have emerged first, followed by some form of genetic molecule that was both structurally simpler and chemically more stable than RNA. Only much later did the mechanisms of RNA genetics and ribozymes come into play. Here are some reasons:
Metabolism, which in its earliest stages uses rather simple molecules in the C–O–H (and maybe S) chemical system, seems vastly easier to jump-start than genetics. By contrast, the RNA World scenario relies on exact sequences of chemically complex nucleotides in the C–O–H–N–P system. Accordingly, modern cells synthesize nucleic acids through metabolism, but RNA synthesis is several steps removed
from the core metabolic cycle, the citric acid cycle. This layering of a simple core metabolism surrounded by successively more complex layers of synthesis suggests that metabolism came first and other chemical pathways were added later.
Many of the presumed protometabolic molecules are synthesized with relative ease in experiments that mimic prebiotic environments, à la Miller–Urey. RNA nucleotides, by contrast, have never been synthesized from scratch, in spite of decades of focused effort.
Even if a prebiotic synthetic pathway to nucleotides could be found, a plausible mechanism to link those individual nucleotides end-to-end into an RNA strand has not been demonstrated. So it’s not obvious how catalytic RNA sequences would have formed spontaneously in any prebiotic environment.
Sometimes you have to place your bets and put your cards on the table. I view the RNA World as a critical, but relatively late, transitional stage that occurred when life was well established on Earth—well after the emergence of a stable, evolving metabolic world, and before the modern DNA-protein world. Biologists seem reasonably confident that the last stages of this evolution—the transition from the RNA World to a DNA-protein genetic system—can be understood. Top-down studies of modern life-forms and the genetic code provide abundant clues about that process.
The greater mystery lies in the seemingly intractable gap between primitive metabolism and RNA. Before we can contemplate the RNA World, therefore, we have to address the pre-RNA World. By what chemical process did the first information-bearing system emerge?