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The Beginnings of Life on Earth

Christian de Duve

Origin and Evolution of the RNA World

As certain as many people are that the RNA world was a crucial phase in life's evolution, it cannot have been the first. Some form of abiotic chemistry must have existed before RNA came on the scene. For the purpose of this discussion, I shall call that earlier phase "protometabolism" to designate the set of unknown chemical reactions that generated the RNA world and sustained it throughout its existence (as opposed to metabolism--the set of reactions, catalyzed by protein enzymes, that support all living organisms today). By definition, protometabolism (which could have developed with time) was in charge until metabolism took over. Several stages may be distinguished in this transition.

In the first stage, a pathway had to develop that took raw organic material and turned it into RNA. The first building blocks of life had to be converted into the constituents of nucleotides, from which the nucleotides themselves had to be formed. From there, the nucleotides had to be strung together to produce the first RNA molecules. Efforts to reproduce these events in the laboratory have been only partly successful so far, which is understandable in view of the complexity of the chemistry involved. On the other hand, it is also surprising since these must have been sturdy reactions to sustain the RNA world for a long time. Contrary to what is sometimes intimated, the idea of a few RNA molecules coming together by some chance combination of circumstances and henceforth being reproduced and amplified by replication simply is not tenable. There could be no replication without a robust chemical underpinning continuing to provide the necessary materials and energy.

The development of RNA replication must have been the second stage in the evolution of the RNA world. The problem is not as simple as might appear at first glance. Attempts at engineering--with considerably more foresight and technical support than the prebiotic world could have enjoyed--an RNA molecule capable of catalyzing RNA replication have failed so far.

With the advent of RNA replication, Darwinian evolution was possible for the first time. Because of the inevitable copying mistakes, a number of variants of the original template molecules were formed. Some of these variants were replicated faster than others or proved more stable, thereby progressively crowding out less advantaged molecules. Eventually, a single molecular species, combining replicatability and stability in optimal fashion under prevailing conditions, became dominant. This, at the molecular level, is exactly the mechanism postulated by Darwin for the evolution of organisms: fortuitous variation, competition, selection and amplification of the fittest entity. The scenario is not just a theoretical construct. It has been reenacted many times in the laboratory with the help of a viral replicating enzyme, first in 1967 by the late American biochemist Sol Spiegelman of Columbia University.

An intriguing possibility is that replication was itself a product of molecular selection. It seems very unlikely that protometabolism produced just the four bases found in RNA, A, U, G and C, ready by some remarkable coincidence to engage in pairing and allow replication. Chemistry does not have this kind of foresight. In all likelihood, the four bases arose together with a number of other substances similarly constructed of one or more rings containing carbon and nitrogen. According to the present inventory, such substances could have included other members of the purine family (which includes A and G), pyrimidines (which include U, T and C), nicotinamide and flavin, both of which actually engage in nucleotide-like combinations, and pterines, among other compounds. The first nucleic acid-like molecules probably contained an assortment of these compounds. Molecules rich in A, U, G and C then were progressively selected and amplified, once some rudimentary template-dependent synthetic mechanism allowing base pairing arose. RNA, as it exists today, may thus have been the first product of molecular selection.

A third stage in the evolution of the RNA world was the development of RNA-dependent protein synthesis. Most likely, the chemical machinery appeared first, as yet uninformed by genetic messages, as a result of interactions among certain RNA molecules, the precursors of future transfer, ribosomal and messenger RNAs, and amino acids. Selection of the RNA molecules involved could conceivably be explained on the basis of molecular advantages, as just outlined. But for further evolution to take place, something more was needed. RNA molecules no longer had to be selected solely on the basis of what they were, but of what they did; that is, exerting some catalytic activity, most prominently making proteins. This implies that RNA molecules capable of participating in protein synthesis enjoyed a selective advantage, not because they were themselves easier to replicate or more stable, but because the proteins they were making favored their replication by some kind of indirect feedback loop.

This stage signals the limit of what could have happened in an unstructured soup. To evolve further, the system had to be partitioned into a large number of competing primitive cells, or protocells, capable of growing and of multiplying by division. This partitioning could have happened earlier. Nobody knows. But it could not have happened later. This condition implies that protometabolism also produced the materials needed for the assembly of the membranes surrounding the protocells. In today's world, these materials are complex proteins and fatty lipid molecules. They were probably simpler in the RNA world, though more elaborate than the undifferentiated "goo" or "scum" that is sometimes suggested.

Once the chemical machinery for protein synthesis was installed, information could enter the system, via interactions among certain RNA components of the machinery—the future messenger RNAs—and other, amino acid-carrying RNA molecules—the future transfer RNAs. Translation and the genetic code progressively developed concurrently during this stage, which presumably was driven by Darwinian competition among protocells endowed with different variants of the RNA molecules involved. Any RNA mutation that made the structures of useful proteins more closely dependent on the structures of replicatable RNAs, thereby increasing the replicatability of the useful proteins themselves, conferred some evolutionary advantage on the protocell concerned, which was allowed to compete more effectively for available resources and to grow and multiply faster than the others.

The RNA world entered the last stage in its evolution when translation had become sufficiently accurate to unambiguously link the sequences of individual proteins with the sequences of individual RNA genes. This is the situation that exists today (with DNA carrying the primary genetic information), except that present-day systems are enormously more accurate and elaborate than the first systems must have been. Most likely, the first RNA genes were very short, no longer than 70 to 100 nucleotides (the modern gene runs several thousand nucleotides), with the corresponding proteins (more like protein fragments, called peptides) containing no more than 20 to 30 amino acids.

It is during this stage that protein enzymes must have made their first appearance, emerging one by one as a result of some RNA gene mutation and endowing the mutant protocell with the ability to carry out a new chemical reaction or to improve an existing reaction. The improvements would enable the protocell to grow and multiply more efficiently than other protocells in which the mutations had not appeared. This type of Darwinian selection must have taken place a great many times in succession to allow enzyme-dependent metabolism to progressively replace protometabolism.

The appearance of DNA signaled a further refinement in the cell's information-processing system, although the date of this development cannot be fixed precisely. It is not even clear whether DNA appeared during the RNA world or later. Certainly, as the genetic systems became more complex, there were greater advantages to storing the genetic information in a separate molecule. The chemical mutations required to derive DNA from RNA are fairly trivial. And it is conceivable that an RNA-replicating enzyme could have been co-opted to transfer information from RNA to DNA. If this happened during the RNA world, it probably did so near the end, after most of the RNA-dependent machineries had been installed.

What can we conclude from this scenario, which, though purely hypothetical, depicts in logical succession the events that must have taken place if we accept the RNA-world hypothesis? And what, if anything, can we infer about the protometabolism that must have preceded it? I can see three properties.

First, protometabolism involved a stable set of reactions capable not only of generating the RNA world, but also of sustaining it for the obviously long time it took for the development of RNA replication, protein synthesis and translation, as well as the inauguration of enzymes and metabolism.

Second, protometabolism involved a complex set of reactions capable of building RNA molecules and their constituents, proteins, membrane components and possibly a variety of coenzymes, often mentioned as parts of the catalytic armamentarium of the RNA world.

Finally, protometabolism must have been congruent with present-day metabolism; that is, it must have followed pathways similar to those of present-day metabolism, even if it did not use exactly the same materials or reactions. Many abiotic-chemistry experts disagree with this view, which, however, I see as enforced by the sequential manner in which the enzyme catalysts of metabolism must have arisen and been adopted. In order to be useful and confer a selective advantage to the mutant protocell involved, each new enzyme must have found one or more substances on which to act and an outlet for its product or products. In other words, the reaction it catalyzed must have fitted into the protometabolic network. To be sure, as more enzymes were added and started to build their own network, new pathways could have developed, but only as extensions of what was initially a congruent network.

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