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CHAPTER 2 THE ORIGIN OF LIFE* S. L. MILLER and N. H. HOROWITZ INTRODUCTION To modern scientists, the origin of life seems one of the most difficult of all problems. This was not always so. From classic Greek times until the middle of the 19th century it was generally accepted that living organ- isms could originate spontaneously, without parents, from non-living material. Thus, for centuries it was believed that insects, frogs, worms, etc. were generated spontaneuosly in mud and decaying matter. This notion was experimentally disproved in 1668 by Redi, who showed that larvae did not develop in meat if adult insects were prevented from laying their eggs on it; but it was revived again following the discovery of microorgan- isms by Leeuwenhoek in 1675. Since bacteria, yeasts and protozoa were much smaller and apparently simpler than any previously known living things, Redi's disproof did not seem to apply to them, and the possibility of then: spontaneous origin became a matter of controversy for nearly 200 years. We know today that these organisms, despite their small size, are enormously complex—as complex as the cells of higher organisms—and the possibility that they could originate spontaneously from non-living material is as remote as it is for any other cells. In a series of brilliant ex- * Parts of this paper are taken with permission from the review by N. H. Horowitz and S. L. Miller, "Current theories on the origin of life," which appeared in Fort- schritte der Chemie organischer Naturstoffe, 20, 423 (1962), edited by L. Zech- meister (Springer-Verlag ). 41

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42 LIFE: ITS NATURE AND ORIGIN periments, Pasteur [1922] in 1861 finally overcame the technical difficulties that had prevented solution of the problem and demonstrated, by logically the same argument that Redi had used, that microorganisms arise only from pre-existing microorganisms. The genetic continuity of living organisms was thus established for the first time. Shortly before, in 1858, Darwin and Wallace had published, simultane- ously and independently, the theory of evolution by natural selection. This theory could account for the evolution from the simplest single-celled organ- ism to the most complex plants and animals, including man. Therefore, the problem of the origin of life involved no longer how each species de- veloped, but only how the first living organism arose. To most scientists, Pasteur's experiments demonstrated the futility of inquiring into the origin of life. It was even suggested that life had no origin, but, like matter, was eternal. Arrhenius [1908] proposed that life- bearing seeds (panspermia) are scattered throughout cosmic space and that they fall on the planets and germinate wherever conditions are favorable. Concern with the origin of life thus faded into the background, while biolo- gists applied themselves to the more profitable task of investigating the nature of living matter. As a result of these investigations, carried out over the last 100 years, the problem can be viewed today in a new light. Biolo- gists have come to realize that life is a manifestation of certain molecular combinations. The origin of life concerns the origin of these molecular combinations, not of the mysterious properties of growth, irritability, me- tabolism, etc. Since, according to cosmologists, not even the elements have existed forever, it is impossible to believe that life has always existed. Bi- ology is therefore faced again with the question of how life arose (cf. Oparin [1957, 1959]). 'One of the reasonably well established facts that we have to start with is that Life did originate on the Earth at some time in the distant past. We shall therefore first consider the nature of living matter from a general point of view and show in what essential properties it differs from inani- mate matter. Next, we will examine the chemical basis for these special properties. We will then turn to the chemistry of the primitive Earth and describe the conditions that are believed to have been present during pre- biotic times. We will finally discuss experiments dealing with the production of biologically interesting compounds under primitive Earth conditions. THE NATURE OF LIVING ORGANISMS Some biologists and biochemists regard the question of how life started as essentially meaningless. They view living and non-living matter as form-

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The Origin of Life 43 ing a continuum, and the drawing of a line between them as arbitrary. Life, in this view, is associated with the complex metabolic apparatus of the cell—enzymes, membranes, metabolic cycles, etc.—and the point at which such a system becomes "alive" is undefinable [Pirie, 1937]. Most biologists, however, are agreed that living matter is uniquely defined by its genetic properties. According to this view, the feature that above all others dis- tinguishes living matter is its mode of duplication. The reproduction of living things differs from the self-propagation that is found in many non- living systems (e.g., the multiplication of crystals, the autocatalytic increase of certain enzymes in the presence of their proenzymes, the growth of a flame) in that it is basically a process of copying. Like the non-living ex- amples mentioned, living organisms select appropriate materials from their environment and transform them into (usually) accurate replicas of them- selves. Kinetically, the reproduction of living organisms is indistinguishable from the autocatalysis of non-living systems; both processes lead to the same mathematical law of autocatalytic increase. They differ fundamentally, how- ever, in that the self-replication of living systems extends to the occasional accidental variants (mutants) which appear from time to time in popula- tions. The mutants copy themselves when they replicate; they do not copy the parental type from which they originated. This remarkable property, which is found only in systems that we call living, is what makes organic evolution possible. Combined with natural selection, it underlies the seem- ingly infinite capacity of organisms to adapt themselves to the needs of their existence. In other words, an organism, to be called living, must be capable of both replication and mutation; such an organism will evolve into higher forms. The concept that the essential attributes of living matter are reproduction with mutation derives principally from the discoveries that have been made in genetics since 1900. Its most cogent expression has been given by Muller [1922, 1929]. One of the most far-reaching genetic discoveries was that the properties of self-replication and mutation (henceforth called genetic properties) are associated with a material substance of the cell which is con- fined largely to the chromosomes. One of the major accomplishments of biochemistry and genetics has been the identification of the genetic material in cells as deoxyribonucleic acid (DNA). The genetic material of a number of bacterial viruses (bac- teriophages) has also been shown to be DNA. In many plant and animal viruses the genetic material is not DNA but ribonucleic acid (RNA). It is now generally agreed that the structure of DNA, as isolated from a variety of cells, is that proposed by Watson and Crick [1953]. The investigations of Kornberg and his associates [1960] on the enzy- matic synthesis of DNA in vitro furnish the most important evidence for

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44 LIFE: ITS NATURE AND ORIGIN TABLE 1. Polymerization of DNA. m AdRPPP + m TdRPPP + n GdRPPP + n CdRPPP I f DNA + Polymerase + Mg*' (AdRP)ra(TdRP)m(GdRP)n(CdRP)n + 2(m + n)PP A = adenine. C = cytosine. P = phosphate. T = thymine. dR = deoxyribose. PP = pyrophosphate. G = guanine. the self-replication of DNA. These workers have obtained an enzyme from bacterial cells that polymerizes the 5'-triphosphates of the four constituent nucleosides of DNA to produce DNA and inorganic pyrophosphate. This polymerization takes place only in the presence of DNA as a catalyst or primer (Table 1). The DNA formed in this reaction is indistinguishable in physical prop- erties from natural, two-stranded, high-molecular weight DNA. Chemical evidence shows that the two strands are anti-parallel, as predicted by the Watson-Crick model. The absolute requirement for a DNA primer and for all four deoxynucleoside triphosphates indicates that the reaction involves the copying of the primer. This is further strengthened by the observation that the base composition of the product is the same as that of the primer for a variety of different DNA's, and is independent of the initial concentra- tions of substrates. It is believed at the present time that the heterocatalytic activity of the genes can be accounted for entirely on the basis of their role in the synthesis of enzymes and other proteins. Considerable progress has been made in recent years in elucidating the synthesis of proteins in cell-free systems, despite difficulties owing to the complexity and lability of the systems. It has been established that the major site of protein synthesis in the cell is in submicroscopic ribonucleo- protein particles of the cytoplasm, the ribosomes. It is believed that ge- netic information from the nucleus is contained in these particles in the form of RNA and that the latter determines the sequence of amino acids in the synthesized protein. Considerable attention has been paid to the mode of activation of the amino acids and to their mode of transfer to the ribosomes. It has been established that activation and transfer require a specific enzyme and a specific ribonucleic acid for each amino acid. It has recently been found that synthetic polyribonucleotides can act as "messenger" RNA in vitro. Thus, when polyuridylic acid is added to a ribosomal preparation from E. coli, it stimulates the system to produce polyphenylalanine [Nirenberg and Matthaei, 1961]. This discovery has

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The Origin of Life 45 TABLE 2. DNA Replication and Control of Protein Synthesis. DNA polymerase DNA -f deoxyribonucleoside triphosphates > 2 DNA + Ribonucleoside triphosphates It "Messenger" RNA Amino acid + ATP + specific "transfer" RNA .J, RNA polymerase ^ specific activating enzyme Ribosome •*- Amino acid . RNA I Protein made it possible to assign trinucleotide code words to most of the amino acids [Speyer et al., 1962; Matthaei et al, 1962]. The similarity between the reactions of gene duplication and of "mes- senger" RNA synthesis is striking. Both involve base pairing and polymeri- zation of nucleoside triphosphates. It is likely that base pairing also operates in the alignment of amino acids in polypeptide synthesis [Hoag- land, 1960]. Table 2 summarizes schematically the autocatalytic and heterocatalytic reactions of DNA. The view adopted here is that the unique attribute of living matter from which all of its other remarkable features derive, is the capacity for self- duplication with mutation. Genetic studies on a variety of organisms have shown that this capacity is confined to material that is largely localized in the chromosomes. Besides directing its own synthesis, the genetic material induces the synthesis of proteins in the cell, including the catalysts that make available the energy and the precursors needed for the perpetuation of the system. The central problem in the origin of life is to account for the origin of material combining these properties. The genetic material of living organisms has been identified as nucleic acid. Of the two nucleic acids, DNA appears to be the principal genetic substance of bacterial viruses, bacteria, and higher plants and animals. RNA is the genetic substance of many plant and animal viruses, and it is not excluded that it has a genetic role in higher organisms. The molecular structure of DNA is such as to suggest a simple mechanism for its replication. This mechanism is supported by experiments in vivo and in vitro. The latter show that replication of DNA can occur in a system containing activated precursors and a single enzyme. The structure of DNA also suggests a molecular basis for mutation, and this, too, is sup- ported by experimental findings.

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46 LIFE: ITS NATURE AND ORIGIN The heterocatalytic action of DNA is mediated by a specific RNA which is synthesized in a DNA-dependent reaction which appears to be very similar in mechanism to the reaction by which DNA itself is replicated. The RNA enters the ribosomes, where it determines, in an unknown man- ner, the amino acid sequence of a specific polypeptide chain. The system described above fulfills the minimal requirements for a living system, as defined earlier. Its discovery and elaboration, starting from the observations of Mendelian genetics, is surely the major accomplishment of twentieth century biology to date. The system is relatively simple, compared to a whole cell, and to this extent it brings us closer to an understanding of the origin of life. Yet it is undoubtedly still too complex and too efficient to have originated spontaneously by random chemical reactions. It is almost certain that this system is itself the product of a long evolution. It can be argued that the present genetic system has evolved so far from the original, primitive genetic system that it bears little resemblance to it. Thus the first genetic system might have utilized nucleic acids with different sugars and different purines and pyrimidines; it might not even have con- tained a sugar-phosphate backbone. It is obvious that other self-replicating polymers might be possible but until specific models are proposed and their plausibility examined relative to the DNA model, the simplest assumption is that the first genetic material was closely related to DNA but probably not identical to it. The answer to this problem may become apparent when we know more about the reactions that took place in the primitive oceans. It is tempting to speculate—and many authors have done so—that the first living organism consisted of a polynucleotide which produced or was associated with a polymerase. Such an entity would be capable of perform- ing only one function—self-replication at the expense of preformed organic compounds (nucleotides) in its environment—but it would have the capa- bility of evolving, by known mechanisms, into a highly complex organism. Crow [1959] has pointed out that the primitive organism need not have functioned very efficiently. Replication need only have been accurate enough to prevent the system from mutating itself out of existence. Natural selection would lower the mutation rate by favoring those mutants whose ratio of correct to wrong copies was greatest. Replication may also have been slow, with perhaps a small polypeptide performing the role of poly- merase. Here, too, selection would favor the discovery of more effective catalysts. The polynucleotide hypothesis is attractive, but it is not so simple as it appears. It is by no means clear how even such a simple organism as a self-duplicating polynucleotide was produced by random chemical com- binations. To obtain a polynucleotide of the required specificity implies that random polymerization of mononucleotides occurred on the primitive

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The Origin of Life 47 Earth on a large scale. This would require the presence of catalysts in the environment to guide the reactions of the activated monomers in the direc- tion of polymer synthesis, as against hydrolysis and other degradations which would otherwise predominate. To obtain these specific catalysts, it might be supposed that catalytically active polypeptides (primitive en- zymes) were formed from the amino acids which there is reason to believe were abundant on the primitive Earth. It is not necessary to assume that these primitive enzymes were as specific or as efficient as modern enzymes; neither is it necessary to assume that they were as large. Recent work has shown that the entire structure of some enzymes is not needed for their activity [Anfinsen, 1959] and it is possible that even a small polypeptide can manifest some catalytic activity. Some authors consider it more likely that the first organisms were not individual molecules, but polymolecular aggregates of one kind or another, separated from the surrounding medium by a definite phase boundary. Thus, Oparin [1957] assumes the formation in the primitive ocean of coacervate droplets containing proteins and other high-molecular weight compounds. These are assumed to have carried out a kind of primitive metabolism, ac- cumulating proteins and other substances from the environment, growing in size, and finally fragmenting into smaller droplets which repeated the proc- ess. The coacervate concept is not useful as a model for the first living organism, because no detailed mechanism has been proposed by which co- acervates can replicate, mutate, and therefore evolve. The DNA mechanism is the only one for which we have both direct evidence and a satisfactory theoretical model at the present time. For reasons stated earlier in this article, we believe that any model of primitive life which neglects to account for the genetic properties of living matter is doomed to failure. The co- acervate concept may, however, provide a possibly useful means for concen- trating specific substances in a small volume, thus increasing their opportunities for interaction. THE ORIGIN OF LIFE ON THE EARTH The Geological Record It is estimated from various methods of dating rocks and meteorites that the Earth was formed about 4.5 to 5.0 billion years ago (4.5 X 109). The first fossils of hard shelled animals occur in the Cambrian which begins about 0.6 billion years ago. Structures that have been found in Precambrian rocks are the fossil remains of algal colonies. A number of Precambrian coals are known, and it likely that they are of biological origin. (For further discussion, see Barghoorn and Tyler [1963]; Barghoorn [1957]).

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48 LIFE: ITS NATURE AND ORIGIN The oldest known fossils are the remains of algal colonies found in South- ern Rhodesia. Their age is at least 2.7 billion years [Holmes, 1954; Macgregor, 1940]. It is likely that life was present before this, but so far no geological evidence is available. Many of the Precambrian rocks have been metamorphosed, and the heat has destroyed most of the fossils that may have been present. However, there are some Precambrian sediments that have not been heated and recrystallized, and these offer a rich field for investigation. There is a period of about 2 billion years, between the origin of the Earth and the occurrence of the first algal fossils, during which the origin and early evolution of life took place. This is almost half of geological time. We are without any knowledge of the biological events that occurred during this period. There is little in the geological record that indicates what the conditions were in the very early Precambrian. The temperatures are not known, but are frequently assumed to be close to the present temperatures. The prin- cipal problem is the composition of the primitive atmosphere. Proposals have been made that the atmosphere was strongly reducing, strongly oxi- dizing, and every variation in between. It is generally agreed that free oxygen was absent. The principal disagreement is whether the carbon in the atmosphere was methane, carbon dioxide or carbon monoxide, and the nitrogen was N2 or ammonia. It has been claimed that the presence of large deposits of ferric iron in the Precambrian demonstrates the presence of oxi- dizing conditions, but this iron may have been oxidized after it was de- posited by oxygen in ground waters. The ferric iron might also have been formed by iron bacteria or by non-biological processes, even though the thermodynamically stable species would presumably be ferrous. Since the geological record tells us very little about the conditions on the primitive Earth and when life arose, we must approach this problem from the standpoint of the origin of the Earth. The Formation of the Earth It is presently held that the planets and Sun were formed at the same time from a cloud of cosmic dust at low temperatures. This spherical cloud of dust and gas collapsed into a round disk due to the forces of rotation and gravitation. The disk, in turn, broke up into sections or rotating segments, and the particles of dust and gases in these cells were pulled together by gravitational attraction until they became solid bodies. The central portion became the Sun, while the sections farther out became the planets. It is clear that most of the gaseous material, particularly the hydrogen, helium,

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The Origin of Life 49 nitrogen (as ammonia), carbon (as methane) and oxygen (as water) es- caped before the Earth was formed. This is true because the Earth con- tains very much less of these elements relative to a non-volatile element such as silicon than does the Sun. In the case of Jupiter and Saturn more of these elements were retained when these planets formed because of the lower temperatures at that distance from the Sun. After the mass of dust and gas becomes dense enough, it acquires a gravitational field that slows up or prevents the escape of the gases in its atmosphere. In the case of the Earth only the two lightest elements, hydro- gen and helium, can escape. The rate of escape is strongly dependent on the temperature and the gravitational field, so that in the case of Jupiter and Saturn, their low temperatures and high gravitational fields make the escape of hydrogen and helium very slow. Therefore, the present atmospheres of these planets are probably not much different from the atmospheres they had when they were formed. The atmospheres of Jupiter and Saturn are observed to contain methane and ammonia, and the presence of hydrogen and helium has been observed indirectly. For a discussion of the forma- tion of the Earth that emphasizes the chemical aspects, see Urey [1952a] and for atmospheres, Urey [1959]. The Primitive Atmosphere It is reasonable to expect that the Earth possessed initially an atmosphere similar to that of Jupiter and Saturn since the Earth was formed from the same dust cloud, but with much less hydrogen and helium. In the case of Venus, Earth and Mars, this atmosphere has been altered by the escape of hydrogen. These planets, smaller and closer to the Sun than the major planets, lose their hydrogen rapidly enough to change the nature of the atmosphere in geological times. The loss of hydrogen results in the production of carbon dioxide, nitrogen, nitrate, sulfate, free oxygen and ferric iron. The over-all change has been oxidation of the reducing atmosphere to the present oxidizing atmosphere. Many complex organic compounds would have been formed during the overall change, thereby presenting a favorable environment for the forma- tion of life. The idea that organic compounds were produced on the primitive Earth under reducing conditions was first clearly stated by Oparin [1937] in his book, The Origin of Life. Urey [1952a, 19526] gave a more detailed statement of the reasons for a reducing atmosphere, and showed by thermo- dynamie analysis that so long as molecular hydrogen is present, methane and ammonia will be the stable forms of carbon and nitrogen.

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50 LIFE: ITS NATURE AND ORIGIN The equilibrium constant (at 25 °C in the presence of liquid water) for the reaction CO2 + 4 H2 = CH4 -|- 2 H2O is 8 X 1022, and therefore any pressure of hydrogen greater than about 10 •' atm. will reduce carbon dioxide to methane. The same is true for graphite. Carbon monoxide is unstable relative to carbon dioxide, hydro- gen, and methane in the presence of water. The carbon dioxide in the atmosphere is kept low by absorption in the oceans to form HCO.3, H2CO3 and CO.j. The carbon dioxide also reacts with silicates, to form lime- stones, for example CaSiO3 + CO2 = CaCO3 + SiO2 K25 = 10" The equilibrium constant for the reaction y2^ + y2^ = NH, is 7.6 X 10*. Ammonia is very soluble in water and therefore would dis- place the above reaction toward the right, giving PH/ = 8.0 X 1013 (H+), where P = partial pressure. This equation shows that most of the am- monia would have been present in the ocean instead of the atmosphere. The ammonia in the ocean would have been stable until the pressure of hydrogen fell below about 10~5 atm., assuming the pH of the ocean was 8, i.e., the present value. From these equilibria it is seen that so long as there is an appreciable amount of molecular hydrogen present, we can say that the atmosphere will consist of methane, ammonia, nitrogen, and water vapor. Carbon monoxide is unstable under these conditions. Carbon dioxide dissolves in the ocean, and it also reacts with silicates to form limestones (CaCO3). As the hydro- gen escapes, the methane and ammonia are dehydrogenated, and this hydro- gen also escapes. In the end this results in the oxidation of the methane and ammonia to carbon dioxide and nitrogen. Finally, the water is photo- chemically dissociated to oxygen and hydrogen. This hydrogen escapes, and free oxygen appears in the atmosphere resulting in a highly oxidizing atmos- phere. This does not mean that thermodynamically unstable gases were entirely absent from the primitive atmosphere, but that they were present only to the extent of a few parts per million. It is asserted by Rubey [1955] that surface carbon of the Earth came from the outgassing of the interior, the carbon being in the form of carbon

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The Origin of Life 51 monoxide and carbon dioxide. This may well have been an important source of the surface carbon, but the more oxidized carbon would be con- verted to methane so long as molecular hydrogen was present. For a more detailed discussion of the equilibria in the primitive atmos- phere, see Miller and Urey [1959]. It has been recently proposed by Lederberg and Cowie [1958], by Fowler, Greenstein and Hoyle [1961] and by Or6 [1961], that the syn- thesis of organic compounds took place before the Earth was formed. Organic compounds have been synthesized at low temperatures from a mix- ture of methane, ammonia and water under conditions possibly present in comets. These compounds include acetylene, ethane, propane and several other hydrocarbons [Glasel, 1961]; and urea, acetamide and acetone [Berger, 1961]. It is quite probable that such syntheses took place in the primitive dust cloud and that much of the carbon was retained on the Earth in this form. Most of these organic compounds were probably de- stroyed by heating during the formation of the Earth. The organic com- pounds thus destroyed would eventually form methane, carbon dioxide and hydrogen, and the surviving organic compounds would undergo further transformations. Therefore the form in which the carbon was retained does not appreciably affect the conditions in the atmosphere and hydrosphere of the primitive Earth. This point is discussed further by Miller and Urey [1964]. The idea that the Earth had a reducing atmosphere is at first difficult to accept, since it is so different from what is now present. It would probably not be necessary to accept the hypothesis of the reducing atmosphere if organic compounds could be synthesized under oxidizing conditions (that is, from carbon dioxide and water) and thereby provide favorable condi- tions for the origin of life. Numerous attempts have been made to synthesize organic compounds under oxidizing conditions. Ultraviolet light and electric discharges do not give organic compounds except when contaminating reducing agents are present [Rabinowitch, 1945]. If a mixture of hydrogen, carbon dioxide and water is used, then organic compounds will be obtained, but only very small amounts of hydrogen could be present under oxidizing conditions. Formic acid and formaldehyde have been synthesized from carbon dioxide and water by using 40 million electron volt helium ions from a 60 inch cyclotron as a source of energy. However, only 10~7 molecules of formalde- hyde were synthesized per ion pair [Garrison et al., 1951]. Although the simplest organic compounds were indeed synthesized, the yields were so small that this experiment can best be interpreted to mean that it would not have been possible to synthesize organic compounds non-biologically as long as the Earth had oxidizing conditions. This experiment is important in

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62 LIFE: ITS NATURE AND ORIGIN heating alkali metal and calcium dihydrogen phosphates above — 300°C. However, metaphosphate minerals are not known to occur in nature. This is not surprising since Ca(H2PO4);, which would be the starting material for a thermal dehydration to calcium metaphosphate, is itself not a known mineral. Pyrophosphate could be formed by a thermal dehydration of Brushite (CaHPO4 . 2H2O) or Monetite (CaHPO4), which are relatively rare minerals, but this apparently does not occur since not a single pyro- phosphate mineral is known [Rankama and Bahama, 1954; Palache et al., 1951]. A low temperature synthesis of pyrophosphate and other high energy phosphates appears to be required. Pyrophosphate has been synthesized from soluble phosphate using cyanamide and its dimer (dicyandiamide) as a source of free energy [Steinman et al., 1964]. The yields were not given. Pyrophosphate has also been synthesized from hydroxy apatite [Ca10(PO4)6(OH)2] andcyanate [Miller and Parris, 1964]. The apatites are by far the most abundant form of phosphorus on the Earth. Apatite is insoluble, as is calcium pyrophosphate, and so this synthesis takes place on the surface of the apatite. The yield of pyrophosphate is a maximum of 27 per cent (at pH = 6.5) of the cyanate added to the system. It appears likely that pyrophosphate was synthesized by such processes. There may have been other processes yet to be outlined that also synthe- sized pyro- and other high-energy phosphates. Enzymes There are many small molecules that act as catalysts for various reactions, and in a number of cases coenzymes have catalytic activity in the absence of the protein. There is an extensive literature on these model enzyme re- actions \Westheimer, 1959]. The primitive enzymes should have more than a simple catalytic activity. These catalysts should be active, they should catalyze one reaction in good yield without a large amount of side reaction, and they should possess some degree of specificity for their sub- strates. It is quite possible that together these requirements are too re- strictive for the primitive catalysts, but some of these requirements would seem to be necessary. The synthesis of such primitive enzymes has not been accomplished, nor does it appear that this problem will be easy. A scheme for the prebio- logical synthesis of enzymes has been proposed by Granick [1957] and Calvin [1956], but no experiments have been carried out. Fox and Krampitz [1964] have shown that polypeptides containing large amounts of lysine will catalyze the decarboxylation of glucose or an intermediate in the decomposition of glucose. The catalyzed reaction is a very small side reaction since the yield of CO2 is about 10~2 per cent of the glucose.

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The Origin of Life 63 However, there may be ways of increasing the yield, specificity, and rate of this catalyst so that it approaches more closely the characteristics ap- parently needed for prebiological catalysts. Coacervates and Microspheres Oparin's model of the first living organism was a coacervate particle that would be able to divide into two or more coacervate particles by absorbing material from the environment [Oparin, 1957]. In the course of time these coacervate particles would acquire the ability to accumulate selectively the desired material from the environment and to divide into two particles that were more and more alike. Although not emphasized by Oparin, it is envisioned that in the course of time a genetic apparatus of DNA would be incorporated into this system. A point of view similar to Oparin's has been expressed by Fox who has synthesized spherical particles about 1 micron in diameter by heating in 1 M NaCl solution the polypeptides formed from the thermal polymeriza- tion of amino acids [Fox et al., 1959; Fox, 1960; Fox and Yuyama, 1963; 1964; Fox and Fukushima, 1964]. Such microspheres may have been formed whether the polypeptides were synthesized by thermal processes or by another mechanism. Fox envisions these microspheres as the pre- cursors to the first living organism. However, the mechanism by which such microspheres could acquire the ability to self-replicate has not been demonstrated experimentally nor even outlined theoretically. As discussed earlier, modern biological advances in our knowledge of the molecular biology of DNA would indicate that the essential point is that of accurate self-reproduction. There is nothing so far in the area of primitive syntheses to indicate that this point of view is in error. Synthesis of Polynucleotides Capable of Self-duplication As indicated earlier, a self-duplicating molecule of DNA would be the first living organism. Kornberg's polymerase enzyme together with the nucleotide triphosphates will carry out this synthesis. Even with the syn- thesis of such an enzyme on the primitive Earth and the presence of the nucleotide triphosphates, such a system could not continue to operate under geological conditions, principally because of the dilution of the precursors. Some structure or mechanism would be necessary to hold the system to- gether, and to provide for the synthesis of the polymerase. It is reasonable to assume some sort of membrane, presumably lipid, to do this task, but there may be other mechanisms. There are no experiments nor even de- tailed hypotheses in this area. Therefore, the problems will not be dis- cussed further here.

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64 LIFE: ITS NATURE AND ORIGIN CONCLUSIONS The experimental work on the synthesis of organic compounds under primitive Earth conditions is lacking in a number of important areas, and a number of the experiments were not carried out under reasonable con- ditions. However, these experiments taken together indicate that large quantities of organic compounds were synthesized on the primitive Earth, and that many of these compounds are those that occur in contemporary living organisms. Compounds that do not occur in present living organisms have not usually been sought in such experiments, principally because it is difficult to decide which "nonbiological" compounds might have been synthesized. In spite of this, it is probably the case that a surprisingly large fraction of "biological" compounds is obtained. It will require a great deal of experimental work to justify this statement. If it proves to be true, then this implies that the first living organism was constructed from the predominant organic compounds in the primitive oceans, while the classes of compounds that were not "useful" were excluded from its structure. This would mean that availability and "usefulness" determined the basic constituents of organisms on the Earth, and that chance did not play the major role in this area. These considerations, although the answers are not yet known, are im- portant for the design of experiments to detect life on Mars. If we accept the above arguments that the components of life on Mars are the same as those in Earth organisms, then the growth medium should be designed accordingly. It is unlikely (but not impossible) that the organisms on Mars will be identical in their basic components. For example, the bio- logical catalysts may be proteins, but it would be surprising if the Martian proteins had the same 20 amino acids as those in Earth organisms. We can, however, make provision in the experimental procedures to anticipate reasonable differences. The discussion in this article is based on conditions that are generally believed to have been present on the primitive Earth. It is clear that the same syntheses would have taken place on Mars if the conditions were similar. We have no certain knowledge of the early conditions on Mars, just as we are not certain in the case of the Earth. However, it is quite probable that the conditions were similar in terms of these planets' reducing character since they were formed from the same cosmic dust cloud. The uncertainty is in whether there was sufficient water initially on Mars and whether there was sufficient time available for life to have started before most of this water escaped. There are also the related questions of the time for life to begin under favorable conditions and the ability of life to

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The Origin of Life 65 survive during drastic changes in the environment. All these questions are best answered by conducting a search for life on Mars. REFERENCES Abelson, P. H. (1956) Amino Acids Formed in "Primitive Atmospheres." Science, 124, 935. Anfinsen, C. B. (1959) The Molecular Basis of Evolution. John Wiley & Sons, New York. Arrhenius, S. (1908) Worlds in the Making. Harper, New York. Bahadur, K. (1954) Photosynthesis of Amino Acids from Paraformaldehyde and Potassium Nitrate. Nature, 173, 1141. Bahadur, K. (1959) The Reactions Involved in the Formation of Compounds Preliminary to the Synthesis of Protoplasm and Other Materials of Biological Importance. In: A. I. Oparin et al., eds., Proceeding of the First International Symposium on the Origin of Life on Earth, p. 140, Pergamon Press, New York. Bahadur, K., Ranganayaki, S., and Santamaria, L. (1958) Photosynthesis of Amino Acids from Paraformaldehyde Involving the Fixation of Nitrogen in the Presence of Colloidal Molybdenum Oxides, as Catalyst. Nature, 182, 1668. Barghoorn, E. S. (1957) Origin of Life. Geol. Soc. Amer., Memoirs No. 67, 2, 75. Barghoorn, E. S. and Tyler, S. A. (1963) Fossil Organisms from Precambrian Sediments. Ann. N.Y. Acad. Sci., 108, 451. Berger, R. (1961) The Proton Irradiation of Methane, Ammonia, and Water at 77°K. Proc. Natl. Acad. Sci. U.S., 47, 1434. Butlerow, A. (1861) Compt. Rend., 53, 145. Calvin, M. (1956) Chemical Evolution and the Origin of Life. American Scientist, 44, 248. Crow, J. F. (1959) Darwin's Influence on the Study of Genetics and the Origin of Life. In: M. R. Wheeler, Biological Contributions, p. 49. Univ. of Texas, Austin. Davidson, D. and Baudisch, O. (1926) The Preparation of Uracil from Urea. J. Am. Chem. Soc., 48, 2379. Evans, W. L. (1942) Some Less Familiar Aspects of Carbohydrate Chemistry. Chem. Rev., 31, 537. Fowler, W. A., Greenstein, J. L. and Hoyle, F. (1961) Deuteronomy: Syn- thesis of Deuterons and the Light Nuclei During the Early History of the Solar System. Am. J. Physics, 29, 393. Fox, S. W. and Harada, K. (1958) Thermal Co-polymerization of Amino Acids to a Product Resembling a Protein. Science, 128, 1214. Fox, S. W., Harada, K. and Kendrick, J. (1959) Production of Spherules from Synthetic Proteinoid and Hot Water. Science, 129, 1221. Fox, S. W. (1960) How Did Life Begin? Science, 132, 200. Fox, S. W. and Harada, K. (1960) Thermal Co-polymerization of Amino Acids in the Presence of Phosphoric Acid. Arch. Biochem. Biophys., 86, 281. Fox, S. W. and Harada, K. (1961) Synthesis of Uracil under Conditions of a Thermal Model of Prebiological Chemistry. Science, 133, 1923.

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66 LIFE: ITS NATURE AND ORIGIN Fox, S. W. and Yuyama, S. (1963) Abiotic Production of Primitive Protein and Formed Microparticles. Ann. N.Y. Acad. Sci., 108, 487. Fox, S. W. et al. (1963) Amino Acid Compositions of Proteinoids. Arch. Biochem. Biophys., 102, 439. Fox, S. W. and Fukushima, T. (1964) Electron Micrographs of Microspheres from Thermal Proteinoid. In: W. L. Kretovich, ed., Problems of Evolutionary and Applied Biochemistry, p. 93. "Nauka" Press, Moscow. Fox, S. W. and Krampitz, G. (1964) Catalytic Decomposition of Glucose in Aqueous Solution by Thermal Proteinoid. Nature, 203, 1362. Fox, S. W. and Yuyama, S. (1964) Dynamic Phenomena in Microspheres from Thermal Proteinoid. Compar. Biochem. Physiol., 11, 317. Garrison, W. M., Morrison, D. C., Hamilton, J. G., Benson, A. A. and Calvin, M. (1951) Reduction of Carbon Dioxide in Aqueous Solutions by Ionizing Radiation. Science, 114, 416. Glasel, J. (1961) Stabilization of NH in Hydrocarbon Matrices and its Rela- tion to Cometary Phenomena. Proc. Natl. Acad. Sci. U.S., 47, 174. Granick, S. (1957) Speculations on the Origin and Evolution of Photosyn- thesis. Ann. N.Y. Acad. Sci., 69, 292. Groth, W. and Weyssenhoff, H. v. (1957) Photochemische Bildung von Amino- sauren aus Mischungen einfacher Gase. Naturwiss., 44, 510. Groth, W. and Weyssenhoff, H. v. (1960) Photochemical Formation of Organic Compounds from Mixtures of Simple Gases. Planet. Space Sci., 2, 79; Also: Ann. Physik., 4, 70 (1959). Harada, K. and Fox, S. W. (1964a) Thermal Synthesis of Amino Acids from Simple Gases. In: S. W. Fox, ed., The Origin of Prebiological Systems, p. 187. Academic Press, New York. Harada, K. and Fox, S. W. (1964*) Thermal Synthesis of Natural Amino Acids from a Postulated Primitive Terrestrial Atmosphere. Nature, 201, 335. Heyns, K., Walter, W. and Meyer, E. (1957) Modelluntersuchungen ziir Bildung organischer Verbindungen in Atmospharen einfacher Gase durch elektrische Entladungen. Naturwiss., 44, 385. Hoagland, M. B. (1960) The Relationship of Nucleic Acid and Protein Syn- thesis as Revealed by Studies in Cell Free Systems. In: E. Chargaff and J. N. Davidson, eds., The Nucleic Acids, 3, p. 349. Academic Press, New York. Holmes, A. (1954) The Oldest Dated Minerals of the Rhodesian Shield. Nature, 173, 612. Horowitz, N. H. and Miller, S. L. (1962) Current Theories on the Origin of Life. Progress in the Chemistry of Organic Natural Products, 20, 423. Johnson, C. B. and Wilson, A. T. (1964) A Possible Mechanism for the Extra- terrestrial Synthesis of Straight Chain Hydrocarbon. Nature, 204, 181. Kornberg, A. (1960) Biologic Synthesis of Deoxyribonucleic Acid. Science, 131, 1503. Lederberg, J. and Cowie, D. B. (1958) Moondust. Science, 127, 1473. Loew, O. (1886) J. Prakt. Chem., 33, 321. Lowe, C. V., Rees, M. and Markham, R. (1963) Synthesis of Complex Organic Compounds from Simple Precursors: Formation of Amino Acids, Amino Acid Polymers, Fatty Acids, and Purines from Ammonium Cyanide. Nature, 199, 219.

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The Origin of Life 67 MacGregor, A. M. (1940) A Precambrian Algal Limestone in Southern Rho- desia. Geol. Soc. South Africa, Trans., 43, 9. Matthaei, J. H., Jones, O. W., Martin, R. G., and Nirenberg, M. W. (1962) Characteristics and Composition of Coding Units. Prcc. Natl. A cad. Sci, U.S., 48, 666. Mayer, R. and Jaschke, L. (1960) Conversion of Formaldehyde into Carbo- hydrates. Liebigs Ann., 365, 145. Miller, S. L. (1953) A Production of Amino Acids Under Possible Primitive Earth Conditions. Science, 117, 528. Miller, S. L. (1955) Production of Some Organic Compounds Under Possible Primitive Earth Conditions. /. Am. Chem. Soc., 77, 2351. Miller, S. L. (1957a) The Mechanism of Synthesis of Amino Acids by Electric Discharges. Biochem. Biophys. Acta, 23, 480. Miller, S. L. (19576) The Formation of Organic Compounds on the Primitive Earth. Ann. N.Y. Acad. Sci., 69, 260. Miller, S. L. and Urey, H. C. (1959) Organic Compounds Synthesis on the Primitive Earth. Science, 130, 245. Miller, S. L. and Parris, M. (1964) Synthesis of Pyrophosphate under Primitive Earth Conditions. Nature, 204, 1248. Miller, S. L. and Urey, H. C. (1964) Extraterrestrial Sources of Organic Com- pounds and the Origin of Life. Problems of Evolutionary and Applied Bio- chemistry, "Nauka" Press, Moscow, p. 357. Muller, H. J. (1922) Variation Due to Change in the Individual Gene. Amer. Naturalist, 56, 32. Muller, H. J. (1929) The Gene as the Basis of Life. Proc. Intn'l Congr. Plant Science, Ithaca 1, 897. Nirenberg, M. W. and Matthaei, J. H. (1961) The Dependence of Cell-free Protein Synthesis in E. coli upon Naturally Occurring or Synthetic Poly- ribonucleotides. Proc. Natl. Acad. Sci. U.S., 47, 1588. Oparin, A. I., Braunstein, A. E., Pasynskii, A. G., and Pavlovskaya, T. E., eds., Boyd, Edinburgh. Oparin, A. I., Braunstein, A. E., Pasynskii, A. G., and Pavlovskaya, T. E., eds., (1959) Proceedings of the First International Symposium on the Origin of Life on the Earth. Pergamon Press, New York. Oro, J., Kimball, A., Fritz, R., and Master, R. (1959) Amino Acid Synthesis from Formaldehyde and Hydroxylamine. Arch. Biochem. Biophys., 85, 115. Oro, J. (1960) Synthesis of Adenine from Ammonium Cyanide. Biochem. Biophys. Res. Comm., 2, 407. Oro, J. and Guidry, C. L. (1960) A Novel Synthesis of Polypeptides. Nature, 186, 156. Or6, J. (1961) Comets and the Formation of Biochemical Compounds on the Primitive Earth. Nature, 190, 389. Or6, J. and Guidry, C. L. (1961) Direct Synthesis of Polypeptides. I. Polycon- densation of Glycine in Aqueous Ammonia. Arch. Biochem. Biophys., 93, 166. Or6, J. and Kamat, S. S. (1961) Amino Acid Synthesis from Hydrogen Cya- nide under Possible Primitive Earth Conditions. Nature, 190, 442. Oro, J. and Kimball, A. P. (1961) Synthesis of Purines Under Possible Primi- tive Earth Conditions. I. Synthesis of Adenine. Arch. Biochem. Biophys., 94, 217.

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68 LIFE: ITS NATURE AND ORIGIN Oro, J. and Cox, A. C. (1962) Non-enzymatic Synthesis of 2-deoxyribose. Federation Proc., 24, 80. Or6, J. and Kimball, A. P. (1962) Synthesis of Purines Under Possible Primitive Earth Conditions. II. Purine Intermediates from Hydrogen Cyanide. Arch. Biochem. Biophys., 96, 293. Or6, J. (1963a) Non-enzymatic Formation of Purines and Pyrimidines. Federa- tion Proc., 22, 681. Oro, J. (19636) Synthesis of Organic Compounds by Electric Discharges. Nature, 197, 862. Or6, J. (1963c) Synthesis of Organic Compounds by High Energy Electrons. Nature, 797,971. Oro, J. (1964a) Prebiological Synthesis of Nucleic Acid Constitutents. In: W. L. Kretovich, ed., Problems of Evolutionary and Applied Biochemistry, p. 63, "Nauka" Press, Moscow. Oro, J. (19636) Stages and Mechanisms of Prebiological Organic Synthesis. In: S. W. Fox, ed., The Origin of Prebiological Systems, p. 137. Academic Press, New York. Palache, C., Herman, H., and Frondel, C., eds. (1951) Dana's System of Mineralogy, 2, 7th Edition, John Wiley & Sons, New York. Palm, C. and Calvin, M. (1962) Primordial Organic Chemistry. I. Compounds Resulting from Electron Irradiation of C14H4. /. Am. Chem. Soc., 84, 2115. Pasteur, L. (1922) Memoire sur les corpuscules organises qui existent dans I'atmosphere. Examen de la doctrine des generations spontan6es. Dans: P. Vallery-Radot, Oeuvres de Pasteur, 2, p. 210, Masson et Cie, Paris. Pavlovskaya, T. E. and Pasynskii, A. G. (1959) The Original Formation of Amino Acids Under the Action of Ultraviolet Rays and Electric Discharges. In: A. I. Oparin, et al., eds., Proc. 1st Intn'l. Symp. on the Origin of Life on Earth, p. 151, Pergamon Press. Pfeil, E. and Ruckert, H. (1961) Formaldehyde Condensations. Formation of Sugars from Formaldehyde by the Action of Alkalies. Liebigs Ann. 641, 121. Pirie, N. W. (1937) The Meaninglessness of the Terms Life and Living. In: J. Needham and D. E. Green, Perspectives in Biochemistry, p. 11, Cambridge Univ. Press. Ponnamperuma, C., Lemmon, R. M., Mariner, R., and Calvin, M. (1963) Formation of Adenine by Electron Irradiation of Methane, Ammonia and Water. Proc. Natl. Acad. Sci. U.S., 49, 737. Ponnamperuma, C. and Mariner, R. (1963) A Possible Prebiotic Synthesis of Purines. Congress of Pure and Applied Chemistry, London, England, July, 1963 (Abstract). Ponnamperuma, C., Mariner, R. and Sagan, C. (1963a) Formation of Adeno- sine by Ultraviolet Irradiation of a Solution of Adenine and Ribose. Nature, 198, 1199. Ponnamperuma, C., Sagan, C., and Mariner, R. (19636) Synthesis of Adenosine Triphosphate under Possible Primitive Earth Conditions. Nature, 199, 222. Ponnamperuma, C. and Kirk, P. (1964) Synthesis of Deoxyadenosine under Simulated Primitive Earth Conditions. Nature, 203, 400. Ponnamperuma, C., et al. (1964) Guanine: Formation during the Thermal Polymerization of Amino Acids. Science, 143, 1449.

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The Origin of Life 69 Rabinowitch, E. I. (1945) Photosynthesis and Related Processes, 1, p. 81, Interscience Publ., New York. Rankama, K. and Sahama, T. G. (1954) Geochemistry, p. 454, Oxford Univ. Press, Oxford. Rubey, W. W. (1955) Development of the Hydrosphere and Atmosphere, with Special Reference to Probable Composition of the Early Atmosphere. Geol. Soc. Amer., Special Paper No. 62, 631. Schramm, G., Grbtsch, H. and Pollmann, W. (1962) Non-enzymatic Synthesis of Polysaccharides, Nucleosides and Nucleic Acids and the Origin of Self- reproducing Systems. Angew. Chem. (Intern. Ed.), /, 1. Speyer, J. F., Lengyel, P., Basilic, C., and Ochoa, S. (1962) Synthetic Poly- nucleotides and the Amino Acid Code, IV. Proc. Natl. Acad. Sct. U.S., 48, 441. Steinman, G., Lemmon, R. M., and Calvin, M. (1964) Cyanamide: A Possible Key Compound in Chemical Evolution. Proc. Natl. Acad. Sci. U.S., 69, 390. Terenin, A. N. (1959) Photosynthesis in the Shortest Ultraviolet. In: A. I. Oparin, et al., 1959, eds., Proc. 1st Intn'l. Symp. on the Origin of Life on Earth, p. 136, Pergamon Press. Urey, H. C. (1952a) The Planets: Their Origin and Development. Yale Univ. Press, New Haven, Conn. Urey, H. C. (19526) On the Early Chemical History of the Earth and the Origin of Life. Proc. Natl. Acad. Sci. U.S., 38, 351. Urey, H. C. (1959) The Atmospheres of the Planets. In: S. Fliigge, ed., Hand- buch der Physik, 52, p. 363, Springer-Verlag, Berlin. Watson, J. D. and Crick, F. H. C. (1953) Molecular Structure of Nucleic Acids. A Structure for Deoxyribose Nucleic Acid. Nature, 171, 737. Westheimer, F. H. (1959) Enzyme Models. In: P. D. Boyer, et al., eds., The Enzymes, I, 2nd Edition, p. 259, Academic Press, New York.

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PART III THE COSMIC SETTING

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