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4 The Origin of Life What sparked the origin of life on the early Earth? As historians, we must gather our records and try to make sense of them. There are, at present, four primary sources of information: (1) the record of the early solar system, as preserved in comets or carbonaceous chondrites and on the surfaces of Mars or the Moon; (2) the record of terrestrial rocks- geology; (3) the record of ancient microorganisms and their physiological activi- ties paleobiology; and (4) the phylogenetic history recorded in the nucleo- tide and amino acid sequences found in living cells—molecular phylogeny. According to the geological record, the Earth appears to be 4.5 billion years old. The oldest extant supracrustal rocks, the Isua formation in Greenland, are 3.8 billion years old, but they are rather strongly metamorphosed. The earliest solid evidence for life is found in stromatolitic formations in West- ern Australia and South Africa, dated as 3.5 billion years old. However, evidence may yet be found that life was present on Earth more than 3.5 billion years ago. Unlike historians, however, in addition to the record, scientists can also take a constructionist approach: they can simulate in the laboratory condi- tions that may have existed on the prebiotic Earth and see what their conse- quences are. Both approaches have been productive, and together they may eventually solve the problem of how life arose on this planet. Following are examples of these two approaches: · Model systems for synthesizing fundamental biochemical monomers: Here, theory is employed—for example, models of the solar nebula and planetary accretion to deduce the likely composition of the early atmo- sphere and then to observe what compounds are produced when this type of mixture is subjected to various forms of energy such as ultraviolet light, shock waves, or coronal discharge. An early example of this approach was 78

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THE ORIGIN OF LIFE 79 the well-known Miller-Urey experiment, in which amino acids were pro- duced when an electric spark was passed through a mixture of methane, ammonia, hydrogen, and water. More recent models of the early Earth suggest a less reducing atmosphere. Evaluation of these alternative models necessitates new conjectures and experiments as to how the biologically important monomers were formed and what substituted for hydrogen as a reductant. · Comparative molecular biology: Here, an attempt is made to deduce the characteristics of the earliest cells and cellular mechanisms by inspect- ing contemporary organisms for features that are common to the three pri- mary lines of descent: eubacteria, archpebacteria, and eukaryotes. The as- sumption is made that any feature found in all three lines was probably present in the ancestral organisms from which the lines derived. · Models for replication: Replication is essential for life. The nature of DNA (deoxyribonucleic acid), a complementary double helix, has inspired a number of experimental models for primitive replication. The most exten- sively studied of these is Orgel's system for template-catalyzed polymeriza- tion of activated nucleotides. However, the discovery of catalytic RNA (ribonucleic acid) has led to several intriguing suggestions as to how RNA could have catalyzed its own replication. A proposal for the templated replication of clays, made by A. G. Cairns-Smith, has inspired some experi- mental model systems that are now being examined. · Models for the origin of gene expression: Since 1963 it has been recognized that one of the most difficult problems in studying the origin of life has been the origin of translation, the process whereby the sequence of nucleotides in a nucleic acid specifies a sequence of amino acids in a poly- peptide. Several suggestions have been made for the origin of this complex coupling mechanism, but these have not been evaluated experimentally. · Comparative planetology: The study of Mars, Venus, and the Moon should help to reconstruct the early history of the Earth. The early history of this solar system often can be read more easily elsewhere than on Earth. The origin and evolution of the solar system must be understood. As dis- cussed in Chapter 3, the exploration of Mars will bear importantly on a perspective of the origins of life on Earth. It must be emphasized that the study of the origin of life is a highly interdisciplinary endeavor, and the most productive work in this field in- creasingly will be done in that context. The recent discovery of catalytic RNA is a case in point. This finding brought new ideas (and practitioners) into the study of origins, but some of the new theories seem inconsistent with the environmental conditions in which the reactions are imagined to have taken place. In this chapter, four major goals are discussed, together with objectives pertaining to these goals. These objectives, as a whole, address models and

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80 THE SEARCH FOR LIFE'S ORIGINS experimental approaches to the study of the origin and evolution of metabo- lism, replication, and translation. GOAL 1: To understand the origin and evolution of metabolism in I. . . . ~ prlml tl ve IJe Jorms. The 1981 report of this committee (SSB, 1981) gave an overview of the nonenzymatic synthesis of biological monomers in an atmosphere of meth- ane, nitrogen, ammonia, and water. A portion of that report follows: Many of the monomers synthesized enzymatically by cells are thought to have originally accumulated spontaneously on Earth as a result of nonenzy- matic reactions. These include amino acids, components of proteins and nu- cleotides, components of nucleic acids (DNA, RNA). This concept derives from many observations that gaseous mixtures, for example, methane, nitro- gen, ammonia, and water, if supplied with energy such as spark discharges, produce the amino acids including those found regularly in proteins. The dis- tribution of monomers so produced is qualitatively and quantitatively similar to that found in carbonaceous meteorites. In addition, most protein amino acids may be produced nonenzymatically starting with simple organic com- pounds such as formaldehyde and hydroxylamine. Furthermore, the abiotic routes of formation of all the components of DNA and RNA are known. Sugars easily form spontaneously from formaldehyde; polymerization occurs under alkaline conditions. The condensation of hydro- gen cyanide in the presence of ammonia produces amino acids as well as the purine nucleotide bases, adenine and guanine, components of all nucleic ac- ids. Cytosine, a base found in nucleic acids, can be readily synthesized from cyanoacetylene. By deamination, cytosine yields another major base of RNA, uracil. Thymine, a major base of DNA, which, in today's genetic code is informationally equivalent to uracil, can be formed from the condensation of uracil with formaldehyde. In the presence of phosphate the phosphorylated forms of the nucleotides of these bases can be produced nonenzymatically. Fatty acids may be formed from carbon monoxide and hydrogen in the pres- ence of nickel-iron catalysts, catalysts that might have been brought in by meteorites. Glycerol is a component of fats that has also been obtained nonen- zymatically in the laboratory by reduction of glyceraldehyde. Glyceraldehyde itself, a common intermediate in cell energy-yielding reactions, may be formed by condensation of formaldehyde under alkaline conditions. Thus, in the 1981 report, the problem of monomer synthesis was consid- ered solved. However, in recent years, reasonable models suggest that the primitive atmosphere of the Earth consisted largely of CO2, N2, and water vapor. At the same time, preliminary studies have indicated that spark discharge in such an atmosphere results in the formation of nitric acid. Hence, the question of the synthesis of organic compounds on the prebiotic Earth is far from settled and must be reexamined. Achieving an adequate level of understanding of these issues entails the

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THE ORIGIN OF LIFE 81 attainment of many objectives, the most important of which are described below. OBJECTIVE 1: To reexamine the prebiotic origin of biomolecules in environments suggested as probable on the primitive earth. ~ , ~ One proposal (discussed in Chapter 3) is that reduced organic compounds were brought to the Earth in comets and meteorites. Another suggestion is that CO2 was photoreduced by ferrous ion (Fe2+) in water. The banded iron formations that are found in the oldest terrestrial rocks (3.8 billion years old) suggest that the photochemistry of Fez+ in water played a significant role on the early Earth. Sulfides in hot springs and ocean vents also have been suggested as possible reductants of CO2. These new possibilities have raised the question of the nature of the earliest metabolism. Did cells first form in an environment where monomers were abundant and then gradually evolve a photosynthetic capacity, or was photoreduction of CO2 and N2 a prerequisite for the first self-replicating entity? It seems likely that the Western Australian stromatolites were formed by photosynthetic organisms, but to what use was the light energy put? These questions require careful study, including detailed comparative analysis of contemporary metabolic pathways. Sulfide may have been abundant on the early Earth, yet it has received little experimental attention with regard to its possible involvement in pre- biotic syntheses. Hydrothermal vents and hot springs are rich in sulfide and have been suggested as sites of prebiotic synthesis. Thiol esters are more reactive than oxygen esters in many reactions and are important in contem- porary biochemistry. OBJECTIVE 2: To explore mechanisms for sequestering biomolecules on a surface or within vesicles (compartmentationJ. The evolution of biological mechanisms makes sense only if they are sequestered from the environment and protected from dilution. This im- plies the adoption of some form of compartment. The membranes sur- rounding contemporary cells are usually based on some form of phospho- lipid. These commonly contain glycerol, fatty acids or alcohols, phosphate, and one of several other possible molecules. However, the prebiotic syn- theses of long-chain fatty acids and alcohols have presented some difficul- ties. This area of study, leading to plausible prebiotic mechanisms for the synthesis of molecules that could have formed vesicles, consistent with present knowledge of the composition of the early atmosphere, is important to understanding the origin of cellular metabolism. Also necessary is the study of reactions of energy-harvesting molecules that could have been encapsulated inside lipid vesicles.

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82 THE SEARCH FOR LIFE'S ORIGINS OBJECTIVE 3: To identify and characterize chemical systems capable of coenzyme functions in a prebiotic context. The role of coenzymes in the evolution of metabolism is important but understudied. Some workers have pointed out that the nucleotidelike struc- ture of many coenzymes suggests that RNA may once have carried a greater variety of functional groups than it does today and may therefore have been a more versatile catalyst: for example, NAD-RNA (nicotinamide adenine dinucleotide and ribonucleic acid) as a potential redox catalyst. These ideas are testable experimentally, because the required molecules can be made with the aid of the enzyme T4 RNA ligase. Other rudimentary coenzyme mechanisms should be sought: for instance, some coenzymes have been activated by A13+ or by absorption on clays. OBJECTIVE 4: To investigate the nature of the earliest type of cellular metabolism. If two disparate groups of organisms evolved from a common ancestor, then characteristics that are common to the two groups probably were pres- ent in the ancestor. For example, the ability to obtain energy from sulfide oxidation is distributed throughout the prokaryotic lines of descent: the archaebacteria and the eubacteria. If the mechanisms of sulfur oxidation in these two groups of bacteria are similar, then barring lateral transfer it is probable that their common ancestor oxidized sulfur in the same way. Fo- cusing on sulfide oxidation is particularly interesting because it likely was abundant on the early Earth, and there is evidence that the earliest known stromatolitic communities were affiliated with hydrothermally active (hence sulfide-rich) environments. GOAL 2: To understand the origin and evolution of replication. Replication is the process whereby a copy is made of a genetic molecule. This must be done in such a way that the information content of the mole- cule is preserved; the parent molecule must somehow serve as a template for its progeny. The replication process is the essence of life. It is widely believed that reactions simpler than, but similar to, nucleic acid replication and protein synthesis appeared very early in the history of life on Earth. Any attempt to provide a chemical model of the evolution of these coupled processes must grapple with a fundamental problem: nucleic acids are molecules that seem ideally suited for replication, whereas poly- peptides seem similarly suited for function. However, at least in contempo- rary systems, nucleic acids cannot replicate without the help of well-defined protein catalysts, and the synthesis of well-defined protein catalysts is im- possible without the direction of nucleic acids. How might a coupled sys- tem of proteins and nucleic acids have started? Various suggestions for the solution of this "chicken and egg" problem have been discussed:

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THE ORIGIN OF LIFE 83 · Early functional proteins replicated directly. They "invented" nucleic acids and were ultimately enslaved by them. · Early nucleic acids or related molecules replicated independently of proteins. They "invented" protein synthesis. Uncoded polypeptides may or may not have been involved in the earliest preceding replication mecha- nlsms. · Nucleic acid replication and genetic coding of proteins convolved. · The first form of life on Earth was based on a self-replicating system that contained neither nucleic acids nor proteins. The suggestion has been made, for example, that it consisted of a family of self-replicating clay particles. The early system gave rise to the nucleic acid/protein system or a A ~ precursor of it. Claims that the spontaneous polymerization of amino acids leads to the formation of long, highly ordered oligomers are implausible. No detailed mechanisms for the residue-by-residue replication of proteins have been suggested, and the possibility that a protein-copying enzyme could evolve spontaneously is unlikely. Thus, the first suggestion above seems unten- able. The "nucleic-acid first" theory has generated a good deal of experimental effort. Nonenzymatic template-directed synthesis has been studied exten- sively, particularly by L. Orgel and his co-workers. It has been established that a preformed template does indeed facilitate the synthesis of its comple- ment, according to the Watson-Crick pairing rules. The template CCCGCCCGCCCGCC facilitates the synthesis of all of the oligomers up to GGGCGGGCGGGCGGG, with exclusively 3'-5' linkages under appropri- ate conditions. The discovery of RNA molecules that catalyze the cleavage and joining of oligonucleotides was revolutionary. Thus, an RNA molecule might be able to function as an RNA polymerase by catalyzing the nonenzymatic template-directed reactions discussed above. If so, a replicating system based on RNA without proteins certainly seems possible. On the primitive Earth, "RNA life," in which RNA molecules catalyzed a limited set of metabolic reactions in addition to RNA replication, may have preceded life as we know it. However, it remains problematic because · as yet there is no known route from a simple prebiotic environment to a self-replicating RNA; · no prebiotic synthesis of ribose has yet been found that does not also produce a wide range of other sugars; · the condensation of ribose with bases would give complex mixtures of products, including L- as well as D-nucleosides, and nucleosides with a- as well as those with p-glycosidic linkages; and · presently known region-specific and efficient syntheses of internu- cleotide bonds require special conditions.

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84 THE SEARCH FOR LIFE'S ORIGINS OBJECTIVE 1: To search for simple organic replicating systems. Template-directed replication with ribonucleotides is the most straight- forward, experimentally accessible, general model of replication. However, even simpler systems warrant experimental study. It would be important to search for simple nucleotidelike monomers and for even simpler "pro- tonucleic acid" models that use inorganic backbones in place of covalently linker1 organic backbones. For example, simpler structures such as glycerol phosphates that carry a heterocyclic base can participate in template reac- tions and form a glycerol pyrophosphate backbone capable of replacing the standard nucleotide backbone. OBJECTIVE 2: To investigate the possible role of RNA catalysis in replication. It is clear that RNA can exhibit catalytic activity, as well as serve as a template in replication. Thus, it seems more likely than ever before that RNA was an important primordial molecule. RNA molecules have been demonstrated to have specific hydrolytic and ligating activities, and they can act as simple polymerases by extending preexisting RNA chains at the expense of other preexisting ribooligonucleotides. RNA can also act as a phosphate monoester transfer catalyst and phosphomonoesterase. Perhaps the earliest form of life capable of evolution was an RNA molecule or had an RNA genome. The enzyme RNase P (ribonuclease P) and the self-splicing RNAs, both involved in posttranscriptional RNA processing, will prove to be the first known members of a longer list of RNAs that carry out, or are associated with, catalysis. Extension of this list is desirable. Experimental surveys of enzymatic activities that have RNA components, or are sensitive to ribonu- cleases, constitute one way to generate a list of activities for investigation. Such surveys should have the widest possible phylogenetic basis. Current methods for the characterization of RNA structures of any com- plexity present a serious limitation in the study of RNA. Development of this area would be facilitated by the dissemination of methods for the syn- thesis of RNAs of known primary structure and by support for single-crys- tal x-ray studies on suitable synthetic models. A systematic set of high- resolution RNA helices, "loops," and "hairpins" would provide a grammar for expressing the structure of more complex RNAs than is now available. Such information has greatly stimulated study of the activities of DNA, and the lack of similar grammar limits the syntax of hypotheses about RNA function. Complementary to this work are methods for predicting and con- firming the solution structures of complex RNA molecules, for example, by two-dimensional nuclear magnetic resonance (NMR). Modern RNA-based organisms, such as viroids and virusoids, have a

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THE ORIGIN OF LIFE 85 style of life and simple molecular structure that seem likely to pose novel and soluble questions about RNA propagation and activity. The positive- strand RNA viruses (in either prokaryotic or eukaryotic hosts) and other freely replicating RNAs are particularly interesting. It is in these molecules that ancient connections between genotype and phenotype may still exist or have been reestablished. That is, these are modern molecules that must replicate, that often participate directly in translation (as messages), and that may also have the potential to carry out catalysis. Where modern cells have preserved ancient biochemical capabilities, it is possible that these processes can be isolated for examination in a virus or small RNA. The isolation, sequencing, and study of small RNAs from the widest possible diversity of cells may well provide new insights into the funda- mental role of RNA in replication. OBJECTIVE 3: To determine the mechanism of clay formation in na- ture and in the laboratory and the possible relevance of clay to replication. Clays were first implicated in the origin of life by the British crystallog- rapher J. D. Bernal in 1951. He considered that monomers such as nucleo- tides and amino acids could be adsorbed from dilute solution onto a clay surface and there polymerized to give proteins and nucleic acids. Clays are made up of various ions embedded in a two-dimensional sili- cate lattice. The elements involved are mainly silicon, oxygen, aluminum, iron, and magnesium. Clays are formed when water causes the chemical weathering of rocks. The concentration of ions in clays is extremely vari- able; the surfaces of clays usually have a net negative charge that is neutral- ized by a positive counter-ion (e.g., Na+, K+, Mg2+, Ca2+, Zn2+, Few+. The mineral theory of the origins of life postulates the existence of a family of clay particles having two remarkable properties. First, they must have surface structures so specific and detailed that they can catalyze the organic reactions necessary to initiate "organic life" (and different clones of clays may differ markedly in their ability to catalyze specific organic reactions). Second, they must be able to replicate to produce "daughters" having the same remarkable catalytic activity. In 1965, Cairns-Smith proposed that the original genes may have been clays. He suggested that the distribution of ions such as magnesium and iron could play the role of the bases of DNA. The "genetic" information would be stored as the distribution of ions in the different layers. The idea was that clays not only could adsorb and catalyze reactions between organic molecules but could, like DNA, replicate. Thus, two sheets of clay would be like the two complementary strands of a DNA molecule. Ion substitu- tions in one clay sheet would give rise to a complementary pattern on the clay synthesized on its surface. If, as with DNA, an error of replication or mutation is possible, then replicating clays could evolve.

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86 THE SEARCH FOR LIFE'S ORIGINS Although experimental evidence in support of these ideas is meager, the committee feels that they merit further study, particularly with regard to template and catalytic aspects of clay lattices. GOAL 3: To understand the origin and evolution of gene expression. The origin of translation- protein synthesis is one of the most difficult problems in studying the origin of life. In this process a sequence of nucleotides in an RNA message codes for a sequence of amino acids in a protein. The complex system of ribosomes, transfer RNAs (tRNAs), and aminoacyl-tRNA syntheses has proven difficult to model. All three primary lines of descent—eubacteria, archaebacteria, and eukaryotes—contain the recognizable elements of a single type of ancestral ribosome. Thus the rep- lication/translation apparatus appears to predate the divergence of these three lines and presumably was present in the "progenote," the earliest cell. The function of the contemporary ribosome is far from understood. One early suggestion, still tenable, was that the ribosome acts to isolate the codon-anticodon interaction from the solvent. The ribosomal proteins dif- fer widely among different organisms, whereas the ribosomal RNA (rRNA) is much more conservative in its sequence and higher-order structure. This suggests that the essence of the translation process lies in rRNA. The process of translation is fundamentally coupled to the genome through the genetic code in all extant organisms. Establishment of this couple must be regarded as an essential event in the emergence of the first true organ- isms from a population of progenitors that lacked it. This development allowed the earliest organisms to express individual identity. To understand the origin of the translation apparatus and the genetic code, comparative molecular studies of extant systems are necessary to gain detailed insight into the essential workings of these processes in modern organisms. This information should allow the construction of meaningful models for primitive versions of the processes that are best tested by a direct study with synthetic polymers, in the tradition of prebiotic chemical studies. OBJECTIVE 1: To determine the origin of codon assignments. There are two classes of theories relating to the origin of the genetic code. Models of the "frozen accident" type suppose that the codon assign- ments arose randomly. Other models hypothesize that particular codon assignments reflect affinities between amino acids and nucleotides. Frozen accident models, by their nature, are not readily testable. How- ever, the notion of a specific relationship between codons and amino acids is. The interaction between amino acids and nucleotides has been under study for some years. These interactions are weak in water, and ways to amplify them, and increase their specificity, are being sought. The necessity

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THE ORIGIN OF LIFE 87 for further activation of the amino acids and proper alignment for polymeri- zation into peptides also constrains experimental models. Proponents of specific association models have argued that studies of the interaction of the aminoacyl-tRNA synthetases with their cognate tRNAs could provide important insights. Numerous biochemical studies of this interaction have been made, but the system is complex and fundamental principles have not emerged. Nonetheless, recent advances in recombinant DNA technology and the synthesis of oligonucleotides, coupled with advanced physical tech- niques, encourage the study of model interactions between polynucleotides and amino acids and peptides. Although it has not been widely appreciated, any stereochemical expla- nation for the codon assignments must be coupled to the molecular mechan- ics of translation. Thus, it has been suggested that early forms of tRNAs may have been able to fold up in such a way that the nucleotides of the anticodon would sit close to the amino acid that is esterified at the 3'- terminus. Because a hydrophobic amino acid tends to have a hydrophobic anticodon, a mutual interaction of the esterified amino acid with its anti- codon might stabilize the amino acid ester bond against hydrolysis. The result would be a preference for a hydrophobic amino acid to remain in the site adjacent to a hydrophobic anticodon. Additional specificity could come from steric or polar interactions between the amino acid side chain and the anticodon nucleotides. Further evidence should be sought for specific interactions of amino acids and amino acid derivatives with their codonic and anticodonic nucleo- tides. Possible amplification of these interactions by the addition, for ex- ample, of micelles, lipid vesicles, or simple oligopeptides should be investi- gated. Following the establishment of the genetic code in the early 1960s, many studies were conducted to determine the universality of the codon assign- ments; however, because of the limited sampling of phylogenetic diversity, these studies revealed no variation among species. Not until the 1980s did sequence studies uncover several variant codon assignments in mitochon- dria. At first, these could be attributed to degeneration of the organelle translation machinery. Subsequently, additional coding variations were found in both prokaryotic and eukaryotic organisms. The extent of variation is still unclear. The existence of deviations from code universality must be reconciled with both the origin of the code and the molecular mechanics of translation. OBJECTIVE 2: To understand the molecular mechanics of translation. The translation apparatus is a complex machine with many component parts, reflecting eons of evolution that have embellished the essential appa- ratus in order to fine-tune the process. The mechanism of translation is of

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88 THE SEARCH FOR LIFE'S ORIGINS central interest to exobiology because it is quite reasonable to assume that, once established, the actual mechanics of translation remained largely unal- tered. This view is supported by comparative studies of ribosomes from all known organisms. However, it also is expected because the nature of evo- lutionary processes is to prefer fine-tuning to drastic revision. The interaction of tRNAs with messenger RNA (mRNA) is clearly a dynamic process. The binding of the aminoacylated tRNA to the mRNA triggers the synthesis of a peptide bond and the subsequent repositioning of mRNA, relative to tRNA, by three nucleotides. Two types of models have been proposed for this process. In the conventional "A site/P site" models, tRNAs are imagined to be relatively static structures that are transferred physically from one location to another, carrying mRNA along with them. "Ratchet" models propose that tRNA enters the ribosome and remains at one location but subsequently undergoes conformational changes that result in the movement of mRNA relative to tRNA. In both models, the actual synthetic step occurs at the 3'-end of the tRNA, which is a considerable distance from the site of the codon-anticodon interaction. In either case, coordination must occur between the synthesis and the "translocation" event. This might be accomplished by kinetic means or, conceivably, by the trans- mission of a signal through conformational changes. Recent results suggest that significant progress in understanding the trans- lation apparatus may be made by studying model systems. It is known, for example, that the anticodon helix and loop alone will bind to 30S and 70S ribosomes in a codon-specific manner but that RNAs smaller than the helix and loop are impaired in ribosomal binding. Likewise, the translational process is known to continue at a low rate without the ancillary factors associated with cellular protein-synthesizing systems. Finally, recent mo- lecular dynamics calculations suggest that the CCA terminus of tRNA may be capable of significant motion. Because recent advances in RNA technology make possible the synthesis of RNAs having a defined sequence, this capability should be used to ex- plore possible models for the primitive translation machinery. The committee believes that knowledge of the molecular mechanics of translation in modern organisms will provide insight into the origin of trans- lation. This belief reflects the evolutionary principle that a fundamental process such as translation is likely to be highly resistant to change in its essential character once it is established. At the least, knowledge of the modern mechanism is basic to understanding the origin of the process. OBJECTIVE 3: To conduct a phylogenetic-comparative dissection of the translation apparatus. The extraordinary conservation of the rRNAs in sequence and higher- order structure, coupled with the discovery of RNA catalysis, makes it a

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THE ORIGIN OF LIFE 89 reasonable speculation that the activities of the ribosome may reside in the rRNAs. Beyond this, the processes of codon-anticodon interaction and movement of the mRNA relative to the ribosome may also require the involvement of parts of the rRNAs. It may be possible to identify which elements of the rRNAs are likely candidates in these processes. For ex- ample, extensive portions of the RNAs are clearly dispensable, as is seen by their absence in mitochondrial rRNAs. In this regard, efforts should con- tinue to elucidate the three-dimensional arrangement of the evolutionarily conserved segments of the rRNAs within the ribosome in order to identify regions that perform an active role in translation. This will require a com- bination of approaches using theoretical and experimental methods. GOAL 4: To determine the evolutionary events leading to the accretion of complex genomes. Current theory argues that early RNA genomes gave rise to DNA genomes, partly because DNA is chemically more stable and, hence, more amenable to storing large numbers of genes. We do not know at what stage in the evolution of cellular replication this might have occurred. Presumably the change from an RNA-based genome to a DNA genome occurred prior to the divergence of the primary lines of evolutionary descent. The earliest cellu- lar unit must already have acquired many genes, as required for replication, energy transduction, and at least a rudimentary translation apparatus. Such complexity may have arisen from the accretion of independently derived genetic elements. It is now evident that modern genomes are remarkably fluid in their composition and that they have evolved, in part, by the incor- poration and shuffling of previously independent genomes. From what is known about modern genomes, it seems that the eukaryotic cell nucleus is significantly different in its organization from that of either the eubacteria or the archaebacteria. Although lateral gene transfer proba- bly has had a prominent role in the evolution of all genomes, the eukaryotic cell nucleus seems particularly susceptible to the acquisition of genes through endosymbiosis. For example, there is ample evidence for the transfer of genes from mitochondrial and chloroplast genomes to the cell nucleus. OBJECTIVE 4: To elucidate the organization and interrelationships of phylogenetically diverse genomes. An earlier report of this committee recommended research on the se- quences of monomers in information-bearing polymers (SSB, 1981~. Now, macrosequencing projects involving large eukaryotic genomes seem inevi- table; the technology is at hand for the detailed mapping of bacterial genomes (the entire Escherichia cold genomic DNA sequence will soon be available); and several mitochondrial and chloroplast genome sequences have been published. In view of the substantial contributions of comparative studies

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9o THE SEARCH FOR LIFE'S ORIGINS of single genes, it is anticipated that insight will come from comparative studies of whole genomes. Data of this type provide the inference of the evolution of genome organization and direct insight into important phenom- ena such as the development of novel pathways and interrelationships be- tween protein families. It is clear that a major commitment for genome analysis will require support from many federal agencies besides NASA. However, important aspects of this major undertaking are within the purview of NASA's pro- gram in planetary biology and chemical evolution: for example, analysis of sequence data from the standpoint of the essential elements of genome structure and its fluidity and the implications of such studies for the origin of life. It will thus be necessary for NASA to establish active liaison with other concerned federal agencies (NIH, NSF, DOE) that are developing programs in genome analysis; seeking ways in which NASA expertise can interdigitate fruitfully. Such interactions might involve developing theo- retical models that bear on genome expression, developing robotics for gene mapping and sequencing, and providing sound experience in data-process- . . . 1ng analysis.