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CHAPTER 10 THE DEVELOPMENT OF RIGOROUS TESTS FOR EXTRATERRESTRIAL LIFE SIDNEY W. Fox The answer to the question of the existence of life on Mars will require adequate criteria and procedures for judging the evidence. Ideally, if several astronauts were to disembark upon the surface of Mars and be greeted by organisms that they could immediately recognize intuitively as living, the problem would be easily and cleanly solved. The question to be put first, however, according to recommendations in this volume, will be one of judging the presence or absence of life by terrestrially monitored instruments and tests on Mars. Furthermore, evolutionary considerations support the belief that life, if any, on Mars might be microbial [Lipmann, 1964] and that microbial life, and the results of natural experiments which simulated but did not constitute life, would be extremely difficult or impossible to distinguish [Fox, 1964a]. Whereas advanced life could be recognized by laymen, a borderline type of life could be a cause of contention among experts. The stage of general evolution on Mars might be a) Prebiological, i.e., purely molecular, b) Microbial, c) Macroorganismic. Until a few years ago, the general view stressed the possibility of a differentiation between various levels of complexity within the molecular stage of evolution, viz., a) small molecules, and b) the complex macromolecules. 213

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214 SOME EXTRAPOLATIONS AND SPECULATIONS The difference between our understanding of small molecules such as amino acids, and macromolecules such as protein, is indeed immense. The thermal model has shown, however, that some of the same reactions that yield amino acids cause their immediate pyrocondensation [Fox, Johnson, and Middlebrook, 1955]. Operationally, therefore, reactions leading to the most complex compounds (and systems) are in some cases simple in a way that has often been precluded in theoretical considerations based on the involved mechanisms or the complicated relevant theories of the structures. Related to the fact that the more advanced an organism the more surely it can be recognized as being alive, is the need for running more than one test on a common sample. The benefits should include economy in use of samples, and reinforcement of inferences from single bits of data. Theoretical discussions of the validity of criteria of life serve as a back- ground for the actual investigations. At this stage in the program of the biological exploration of Mars attention should, pragmatically, be on tests that can be performed by devices from which the results can be tele- metered to Earth. Even more realistically, constraints based on the number of bits of information required, and the apportionment of total available bits among the various tests finally selected, are practical considerations in the solution of the problem as a whole. In laboratory experiments performed in attempted imitation of molecular evolution in nature, many of the criteria that have been employed in identifying life have been satisfied [Fox, 1964a], whether these be micro- molecular, macromolecular, or cellular. Since so many vital phenomena have recently been imitated under conditions that might occur on one or more planets, it seems imprudent to deny the possibility that other such phenomena might similarly emerge spontaneously. If one does not assume a discontinuity between prelife and life, mechanistic and evolutionary rea- soning would also lead to the same conclusion. Accepting the above emphasis, one is then led to the next question, namely, how may such criteria be ramified or otherwise improved to yield sufficiently rigorous answers that will not be distorted by the products of natural experiments? To use in advance a premise derived from extended study of the problem, we may seek especially those tests that will be posi- tive only if Darwinian selection has occurred. POTENTIALLY USEFUL CRITERIA OF LIFE Criteria of life that may be useful will be listed in this section. Brief mention of the appearance of such phenomena in synthetic systems pro-

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The Development of Rigorous Tests for Extraterrestrial Life 215 duced under geologically plausible conditions will be made, to provide an understanding of the need for rigorous tests. Ways in which some of these tests may be studied for further development will be discussed in a later section. Biochemical Staples The presence of key biochemical compounds has been considered as a test for life on Mars. Under geologically plausible conditions, however, carbohydrates such as deoxyribose [Ord and Cox, 1962], several amino acids [Miller, 1953], pyrimidines such as adenine [Ord and Kimball, 1961], uracil [Fox and Harada, 1961], guanine \Ponnamperuma et ai, 1964], almost all of the protein-bound amino acids [Harada and Fox, 1964], adenosine triphosphate [Ponnamperuma, 1964], and porphyrins [Kramovskti and Umrikhina, 1964] have been produced in the laboratory. Macromolecules Poly-a-amino acids that are practically indistinguishable from terrestrial bioprotein have been produced from amino acids [Fox and Harada, 1958]. Polynucleotides of limited size have been produced from mononucleo- tides and ethyl metaphosphate (an unnatural reagent) [Schramm, 1964], and from polyphosphoric acid and cytidylic acid [Schwartz and Fox, 1964]. Further study seems more likely to yield larger synthetic macro- molecules than to yield a surer criterion based on the polynucleotide structure. Coding ability has been claimed for the synthetic polynucleotide [Schramm, 1964]. Whereas the origin of the necessary mononucleotides has not been shown comprehensively, the fact that adenosine mono- and triphosphate AMP and ATP can be produced [Ponnamperuma, 1964] suggests the likelihood of similar possibilities for the monophosphates of guanine, cytosine and uracil. Ordered Macromolecules Although Oparin [1964] and others assume that a primitive protein would be "disorderly," thermal poly-a-amino acids, containing 18 or fewer types of amino acids, prove to be ordered as judged by comparison of total composition and terminal compositions [Fox, 1960]. Coding Relationship Between Macromolecules As already stated, coding function has been claimed for synthetic polymers of mononucleotides (Matthei by Schramm in Schramm [1964]).

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216 SOME EXTRAPOLATIONS AND SPECULATIONS Also, an altered balance between total composition and N-terminal compo- sition in thermal poly-a-amino acids when phosphoric acid is included in the reaction mixture has been shown [Fox and Harada, 1960a]. The phosphoric acid does not enter into the product. Accordingly, if one were to compare the results of terminal amino acid composition and total amino acid composition of poly-a-amino acids in samples from Mars and then find, by laboratory experiments, that the products did not have the same analytical values as those prepared simply by heating a-amino acids in the laboratory, he would not be able to conclude that this governance of order was due to terrestrial-type nucleic acids. Ordinary phosphoric acid or, conceptually, other materials might have been responsible for yielding a type of order that could not be attained by the amino acids themselves. Catalytically Active Macromolecules The ability of thermal proteinoids to catalyze hydrolysis of p-nitrophenyl acetate was reported in 1962 [Fox, Harada, and Rohlftng, 1962; Noguchi and Saito, 1962]. The capacity of such macromolecules for the breakdown of natural substrates such as glucose —» glucuronic acid —» carbon dioxide has recently been reported [Fox and Krampitz, 1964]. Unpublished ex- periments show also that many other natural substrates, such as urea, are broken down in aqueous solution by thermal proteinoids [Krampitz, Harada, and Fox, 1964]. Combinations of zinc and proteinoid split ATP, and this activity can be incorporated into microbially sized units [Fox, 19646]. In this general context, one should bear in mind that Siegel [1957] showed that a mineral, chrysotile, catalyzes the decomposition of hydrogen peroxide and of glucose-1-phosphate. Antigenicity Antigenicity has not as yet been found in thermal proteinoids; this is probably the only significant, testable property found in proteins that is lacking in thermal proteinoids. However, a search for this property, which has been cooperative between two laboratories, was not carried out in a rigorous fashion, and deserves to be started again. Meanwhile, studies of Leuchs' poly-a-amino acids have demonstrated, in at least four labora- tories, that chemically synthesized poly-o-amino acids can be antigenic [Stahmann, 1962; Sela, 1962; Maurer, 1962; Gill and Doty, 1962]. Ac- cordingly, the finding of antigenicity in spontaneous Martian poly-a-amino acids would not be an indication of life.

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The Development of Rigorous Tests for Extraterrestrial Life 217 The total number of tests that are positive for both proteins and thermal proteinoids is now between fifteen and twenty, the exact number depending upon how the criteria are classified [Fox, 1963]. The criterion which has not yet yielded the same result on both protein and proteinoid is that of antigenicity. Helicity, also, has not yet been demonstrated in thermal poly-a-amino acids although it has been found and studied extensively in Leuchs' poly-a-amino acids [Blout, 1962]. The test that might feasibly be used for helicity, however, is that of hypochromicity. This test is positive for many thermal poly-a-amino acids due to the somewhat un- stable imide linkage [Rohlfing, 1964]. Structured Proteinaceous Microparticles This heading connotes more than one criterion. The manner in which microparticles which appear as cocci has been demonstrated, under con- ditions that exist terrestrially, and which in earlier eons might have been even more common [Fox and Yuyama, 1963a]. As one example of the degree of control in the laboratory of the composition of formed units, microspheres have been produced under geologically plausible conditions [Fox and Yuyama, 19636] in either the Gram-positive or the Gram- negative state, at will. Stear n and Stear n [1924] ascribed the Gram- staining of bacteria to their protein content. The simultaneous presence of protein-like quality and bacterial morphology is thus illustrated. Configurational One-Sidedness or Net Optical Activity A number of experimental demonstrations that lead to inferences about the origin of optical activity in the absence of cells has been reported in the literature [Fox, Joseph, and Vegotsky, 1956; Wald, 1957; Northrop, 1957; Harada and Fox, 1962]. Two examples are spontaneous resolu- tion [Fox, Johnson, and Vegotsky, 1956] and the stereoselectivity favored in polymerization [Wald, 1957]. Morphological Variety The forms that have been produced spontaneously from thermal poly-a- amino acids are several. Especially do microspherical units appear. These resemble cocci in size and shape (Figure 1) [Fox and Yuyama, 1963a]; they also resemble diplococci, tetracocci cilia, yeast-like buds, etc. (Figure 2).

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218 SOME EXTRAPOLATIONS AND SPECULATIONS OCR for page 213
The Development of Rigorous Tests for Extraterrestrial Life 219 to have at least one metabolic pathway of their own, i.e., glucose ->• glu- curonic acid -> carbon dioxide [Fox and Krampitz, 1964]. Other enzyme- like activities (unpublished) are being found in the polymers. These are weak, in comparison to contemporary enzymes, and possibly both the strength of individual activities and the ramified involvement of metabolic pathways in the contemporary cell can be used to distinguish life on Mars. However, evidence is at hand for some moderately strong catalytic activi- ties in proteinoids; no statement can yet be made as to how diverse and ramified these may be. The practical question may prove to be one of how much extraterrestrial testing of this type is feasible in a single mission. Again, the allowable number of bits of information may impose severe limits. Insofar as evidence of respiration in microbes is concerned, the pro- teinoid microspheres convert glucose to carbon dioxide, aIbeit at a low rate in the experiments performed to date [Fox and Krampitz, 1964]. Growth Enlargement in size of the microspheres and of "buds" on microspheres [Fox, Joseph, and McCauley, 1964] is now documented on film, although not published. Time-lapse pictures of the growth of a "bud" on a micro- sphere have been published but not designated as such in the paper inas- much as no confirming pictures were available at the time [Fox and Yuyama, 1964]. Such confirmation has since been obtained [Fox, Joseph, and McCauley, 1964]. Fission The separation of microspheres into two "daughter" halves has been demonstrated [Fox and Yuyama, 1964]. Septate division is produced by the simple process of raising the pH of a suspension of proteinoid micro- spheres by 2-3 pH units. The fission occurs in typically 30-120 minutes. Figure 3. Electron micrograph of section of osmium tetroxide-stained proteinoid microspheres. Marker—1 micron. 00-

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220 SOME EXTRAPOLATIONS AND SPECULATIONS Although not published, complete separation of the halves into individual microspheres has been recorded on film. Proliferation In accord with the last sentence, the number of individual particles increases and proliferation is thereby signalled. Osmotic Behavior Microspheres shrink in response to hypertonic solutions, and swell in the presence of hypotonic solutions [Fox, Harada, and Kendrick, 1959]. This property is much less pronounced than in biological cells, but would be difficult to interpret in attempts to study osmosis in cells on Mars. Active Transport No study has been made of this property in the kind of synthetic system being discussed. Excretion No search has been made for this concomitant of life in the kind of synthetic system discussed here. Bilamellarity of Membrane Electron microscope studies have revealed that proteinoid microspheres have double layers (Figure 4) [Fox and Fukushima, 1964; Fox, 1964a], Figure 4. Double layers in electron micrograph of section of proteinoid microspheres subjected to elevated pH.

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The Development of Rigorous Tests for Extraterrestrial Life 221 and, in fact, that electron micrographs of sections of osmium tetroxide- stained microspheres are virtually indistinguishable from electron micro- graphs of sections of bacteria such as Bacillus cereus [Murray, 1960]. Energy Transfer A rigorous demonstration of energy transfer in microspheres is not at hand. The incorporation of the ability to split ATP suggests, however, the possibility that this effect may be demonstrated. Irritability This property has not been demonstrated or found in truly synthetic systems of the kind here described. Motility Simulations of motility have been caught in unpublished cinematomicro- graphic sequences [Fox and McCauley, 1963]. This "motility" requires asymmetric particles containing zinc and ATP in the suspension. One sequence is very suggestive of a protozoan in the search for food, and simply "looks alive" to many biologists and nonbiologists. Regeneration This attribute has not been demonstrated, nor sought in the synthetic particles. Mutability The quality of mutability is likely to require an involved form of testing. Any judgment on the extent to which this criterion could be operationally valid would depend first upon the manner in which the criterion could be reduced to a feasible test. The question of simulability would then depend upon the nature of the test. This criterion is also closely related to the general process of Darwinian selection, mentioned earlier. Death A criterion that has, perhaps, received less attention in this context than it merits is that of death. In practice, this would require the cessation of one or more positive tests for life. In practice, death of a living particle might be induced by added poison. The quality of death is capable of being imitiated by the synthetic coccoidally shaped and sized particles.

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222 SOME EXTRAPOLATIONS AND SPECULATIONS For example, the simulation of motility can be arrested by exhaustion of ATP in the suspension or by poisoning with high concentrations of sodium chloride. SUMMARY OF CRITERIA While some of the attributes of living things have not yet been found in synthetic microparticles produced from thermal poly-a-amino acids, many have. Most of those listed have been incorporated by guided ex- periments or have been found unexpectedly, e.g., double layers in the boundary. Most of the criteria listed have been met by the synthetic ex- periments. Inasmuch as so many criteria have been fulfilled, denial of the possibility that others may be met is deemed imprudent. The same conclusion can be reached on the basis of theoretical materialistic reason- ing. The conditions employed in the laboratory are unprecedentedly simple and geologically plausible [Fox, I964a, b, c]. Terrestrial geological plausi- bility is, however, not necessarily equivalent to "geophysical" plausibility for Mars. Answers to the many questions raised in this context require a closer study of Mars. The comments on this point apply especially to the microbial type of life and its imitation by natural experiments. As the level of life becomes increasingly the product of Darwinian selection, the tests are more easily susceptible to heightened rigor. The conclusions derivable from the synthetic model are consistent with a descriptive definition of life by Calvin [1962]: What is a Living System? In any discussion of such a broad all-encompassing subject as this, we are always faced with the problem of trying to define the material system to which we are willing to attribute the adjective 'living'. Personally, I feel that this has a certain degree of subjective arbitrariness about it, since there are those who would be willing to allow the use of this term for systems which would not be accept- able to others. This peculiar characteristic of the problem imme- diately allows us to recognize that the qualities, or properties, which we require of a material system are of the nature of a continuous aggregation in time along which no sharp line of demarcation need necessarily exist.

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The Development of Rigorous Tests for Extraterrestrial Life 223 Similarly, Professor John Keosian [1964] has stated in his recent book, The Origin of Life: This apparent confusion reflects the necessity of recognizing the gradual transition of matter into higher and higher levels of organi- zation embodying newer and more complicated properties. . . . What is important is not an exact definition of life at the borderline on which we can all agree, but rather the recognition of the existence of increasing levels of organization of matter and the understanding of the mechanisms which operate to bring these about. THE PHYSICAL CONDITIONS ON THE EARTH AND ON MARS Examination of terrestrial geology reveals that the physical conditions necessary for the thermal sequence of primordial gases ->. amino acids -> preprotein ->. precells exist in moderate abundance now and were very likely far more abundant during the earlier history of the Earth. Assump- tions of the opposite sort have been made, but the geological opportunity for parts of the thermal sequence is related to the fact that even now over 450 active volcanoes exist on the surface of the Earth; with each active volcano, regions of subvolcanic temperature through the optimum of about 150°C, and above, are associated. Such temperatures are found also in regions not having active volcanoes. The widespread nature of such thermal conditions is documented by Professor Fred M. Bullard who states in his book, Volcanoes [1962]: The average person may think that lavas are something rather rare on the earth's surface. To dispel this idea, he needs only to consider, in addition to the lava flows from individual volcanoes, the great plateau basalts such as those which make up the Columbia River Plateau of the Pacific northwest of the United States. Here, covering most of Oregon and parts of Idaho and Washington with an area of 200,000 square miles, are basaltic lavas reaching a thickness of 3,000 feet and representing hundreds of flows superimposed one upon another. When one realizes also that this is but one of many such areas of the earth he obtains some appreciation of the tre- mendous quantity of lava on the earth's surface. No more esoteric contribution than rain would be necessary for bringing about the step of self-organization of formed systems from polymers arising in thermal zones. The likelihood of pertinent conditions on Mars is more difficult to

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224 SOME EXTRAPOLATIONS AND SPECULATIONS assess for two reasons. One is our lack of knowledge of the Martian facts. (Urey [1961] has stated "Even on Mars it seems likely that there is less volcanic activity than on Earth.") The other is that the limits of conditions necessary for the individual reactions have not been established in the laboratory. EXAMPLES OF POTENTIAL DEVELOPMENT OF RIGOR IN TESTS FOR EXTRATERRESTRIAL LIFE The ways in which the various criteria for detecting life might be made more rigorous are numerous. The laboratory studies indicated as conse- quences of such considerations are even more numerous and ramified. A sampling of possibilities is presented in this final section. Optical Activity Improvement in the use of optical activity as a criterion of life can be visualized in several steps: a) The optical activity might be shown to be associated with com- pounds of carbon. b) The optical activity might be shown to be associated with individual members of a class of biochemical substance, e.g., amino acids or monosaccharides. c) If b could be shown to be referable to a single configuration type, optical activity would be a far more convincing manifestation of life. d) An L isomer of an animo acid is decomposed by a sample of the Martian crust whereas the D enantiomorph is not, or vice versa. Such a result as b, c, or d might indicate Darwinian selection at the microbial level. Evidence of Darwinian selection would, of course, be an indication that life had progressed beyond the initial stage. The fact that these refinements can be visualized may be taken as an argument that the unqualified observation of net optical activity is a highly inadequate criterion. Catalytic Activity This criterion has lost some prestige as a criterion of life. As one example of possible confusion, Siegel [1957] showed that the decomposition of glucose-1-phosphate or of hydrogen peroxide is accelerated by the mineral,

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The Development of Rigorous Tests for Extraterrestrial Life 225 chrysotile. Other comparable demonstrations have been made by others. The demonstration of a network of catalytic activities in formed units would carry more conviction. Highly specific proteolytic activity might be suggestive of enhanced activity attainable by Darwinian selection for the significant function of feeding. Ordered Macromolecules The evaluation of order requires careful definitions of "order," "ran- dom," etc. The statistician's definition of a random sample is one in which each element in the whole population is equally represented. One can extend this definition to the sequence in a population of protein molecules. In a random polyamino acid, each kind of amino acid would thus be repre- sented in each position in the polypeptide chain in proportion to its percent- age in the total composition. Any other distribution would then be nonrandom, or, to some degree, ordered. Such evaluations permit operational investigation, e.g., one may compare C-terminal analyses or N-terminal analyses of amino acids with total com- position. Such comparisons have been made in many analyses of thermal poly-a-amino acids. The examinations show considerable disparities be- tween C-terminal and N-terminal analyses and total compositions. The distribution of amino acid residues, by type, in thermal poly-a-amino acids is accordingly nonrandom. This degree of ordering must be ascribed to the interacting amino acids. In other words, some information is inherent in the monomers. A derivative question is whether the influence of nucleic acids or another coding system can be invoked as a criterion of life. Operationally, one might visualize the recognition of such an "outside" coding influence through a different balance of terminal and total compositions. The rele- vant experiment has, in a sense, been done. Amino acids have been thermally polymerized in the presence of phosphoric acid, which does not enter into the product [Fox and Harada, 1960fo]. The balance of terminal and total compositions differs between the phosphoric acid product and the control without phosphoric acid. One could not use this criterion, then, to differentiate between terrestrial pre-protein on one hand, and protein made by a Martian microbe. The development of a more rigorous criterion of cellularly determined or RNA determined order in polyamino acids may emerge from further studies of total composition and terminal composition in synthetic polymers and in proteins. An extensive laboratory and computer program could be constructed. The starting point for such studies might best be the kind of analysis that is most likely to be feasible in an extraterrestrial study. This

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226 SOME EXTRAPOLATIONS AND SPECULATIONS is perhaps the comparison between total amino acid composition and ter- minal amino acid compositions. If such analyses of unfractionated protein of biological origin were shown to give a balance sheet not attained in synthetic poly-a-amino acids (many such data are already at hand [Fox, Harada, Woods, and Windsor, 1963] ), a basis for a test would be at hand. If a sample of organic material on Mars were shown to have a polyamino composition falling into the terrestrial range of protein and outside the range of the synthetic poly-o-amino acids, the indication of life could be regarded as powerful. The possibility of such a distinctive range of analyti- cal specifications has yet to be established, and would constitute much of the research. Morphology Many instances of simulation of microbial morphology at the associated cellular, cellular, optical micrographic, and electronmicrographic level in synthetic systems have been observed [Fox and Yuyama, 1963a; Fox, 1964a]. Morphologies involving limb systems, etc., would, however, seem to require Darwinian selection. These latter should probably be considered as rigorous criteria of life. Fuller understanding of what forms might be assumed by spontaneously synthetic systems, however, requires further research. REFERENCES Blout, E. R. (1962), The dependence of the conformation of polypeptides and proteins upon amino-acid composition. In: M. A. Stahmann (Ed.) Poly- amino Acids, Polypeptides, and Proteins, University of Wisconsin, 275-279. Bullard, F. M. (1962), Volcanoes, University of Texas Press, p. 55. Calvin, M. (1962), Communication: From molecules to Mars. Bull. Am. Inst. Biol. Sci. 12, 29-44. Fox, S. W. (1960), How did life begin? Science 132, 200-208. Fox, S. W. (1963), Experiments suggesting origins of amino acids and proteins. In: ]. Kastelic, H. H. Draper, and H. P. Broquist (Eds.) Protein Nutrition and Metabolism, University of Illinois College of Agriculture, 141-154. Fox, S. W. (1964o), Experiments in molecular evolution and criteria of extra- terrestrial life. BioScience 74(12),13-21. Fox, S. W. (1964i), Simulated natural experiments in spontaneous organization of morphological units from proteinoid. In: S. W. Fox (Ed.) The Origins of Prebiological Systems, Academic Press, 361-382. Fox, S. W. (1964c), Thermal polymerization of amino-acids and production of formed microparticles on lava. Nature 201, 336-337. Fox, S. W. and T. Fukushima (1964), Electron micrographs of microspheres from thermal proteinoid. In: V. L. Kretovich, T. E. Pavlovskaya, and G. A.

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The Development of Rigorous Tests for Extraterrestrial Life 227 Deborin (Eds.) Problems of Evolutionary and Industrial Biochemistry, "Nauka" Publishing House, 93-100. Fox, S. W. and K. Harada (1958), Thermal copolymerization of amino acids to a product resembling protein. Science 128, 1214. Fox, S. W. and K. Harada (1960a), Thermal copolymerization of amino acids in the presence of phosphoric acid. Arch. Biochem. Biophys. 86, 281-285. Fox, S. W. and K. Harada (19606), The thermal copolymerization of amino acids common to protein. /. Am. Chem. Soc. 82, 3745-3751. Fox, S. W. and K. Harada (1961), Synthesis of uracil under conditions of a thermal model of prebiological chemistry. Science 133, 1923-1924. Fox, S. W. and G. Krampitz (1964), The catalytic decomposition of glucose in aqueous solution by thermal proteinoids. Nature 203, 1362-1364. Fox, S. W. and S. Yuyama (1963a), Abiotic production of primitive protein and formed microparticles. Ann. N. Y. Acad. Sci. 108, 487-494. Fox, S. W. and S. Yuyama (19636), Effects of the Gram stain on microspheres from thermal polyamino acids. /. Bacteriol. 85, 279-283. Fox, S. W. and S. Yuyama (1964), Dynamic phenomena in microspheres from thermal proteinoid. Comp. Biochem. Physiol. 11, 317-321. Fox, S. W., K. Harada, and J. Kendrick (1959), Synthesis of microscopic spheres in sea water. International Oceanographic Congress preprints, 80-81. Fox, S. W., K. Harada, and D. L, Rohlfing( 1962), The thermal copolymeriza- tion of a-amino acids. In: M. Stahmann (Ed.) Polyamino Acids, Poly- peptides, and Proteins, University of Wisconsin Press, 47-54. Fox, S. W., J. E. Johnson, and M. Middlebrook (1955), Pyrosynthesis of aspartic acid and alanine from citric acid cycle intermediates. J. Am. Chem. Soc. 77, 1048-1049. Fox, S. W., J. E. Johnson, and A. Vegotsky (1956), On biochemical origins and optical activity. Science 124, 923-925. Fox, S. W., K. Harada, K. Woods, and C. R. Windsor (1963), Amino acid compositions of proteinoids. Arch. Biochem. Biophys. 102, 439-445. Gill, T. J., HI and P. Doty (1962), The immunological and physio-chemical properties of a group of linear-chain synthetic polypeptides. In: M. A. Stahmann (Ed.) Polyamino Acids, Polypeptides, and Proteins, University of Wisconsin Press, 367-378. Harada, K. and S. W. Fox (1962), A total resolution of aspartic acid copper complex by inoculation. Nature 194, 768. Harada, K. and Fox, S. W. (1964), Thermal synthesis of natural amino-acids from a postulated primitive terrestrial atmosphere. Nature 201, 335-336. Keosian, J. (1964), The Origin of Life, Reinhold Pub. Corp., p. 7. Krampitz, G., K. Harada, and S. W. Fox (1964), Unpublished experiments. Krasnovskii, A. A. and A. V. Umrikhina in comment by A. I. Oparin (1964). In: S. W. Fox (Ed.) The Origins of Prebiological Systems, Academic Press, 252-253. Lipmann, F. (1964), Projecting backward from the present stage of evolution of biosynthesis. In: S. W. Fox (Ed.) The Origins of Prebiological Systems. Academic Press, 259-280. Maurer, P. H. (1962), Immunological studies with synthetic polymers. In: M. A. Stahmann (Ed.) Polyamino Acids, Polypeptides, and Proteins, University of Wisconsin Press, 359-366.

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228 SOME EXTRAPOLATIONS AND SPECULATIONS Miller, S. L. (1953), A production of amino acids under possible primitive earth conditions. Science 117, 528-529. Murray, R. G. E. (I960), The internal structure of the cell. In: I. C. Gunsalus and R. Y. Stanier (Eds.) The Bacteria, 1, Academic Press, p. 91. Noguchi, J. and T. Saito (1962), Studies on the catalytic activity of synthetic polyamino acids having an imidazole group in the active site. /// M. A. Stahmann (Ed.) Polyamino Acids, Polypeptides, and Proteins, University of Wisconsin Press, 313-328. Northrop, J. H. (1957), Optically active compounds from racemic mixtures by means of random distribution. Proc. Nat'l. Acad. Sci. U. S. 43, 304-305. Oparin, A. I. (1964), The Chemical Origin of Life, Charles C Thomas, Spring- field, III. Oro, J. and A. C. Cox (1962), Non-enzymic synthesis of 2-deoxyribose. Federation Proc. 21, SO. Oro, J. and A. P. Kimball (1961), Synthesis of purines under possible primitive Earth conditions. Arch. Biochem. Biophys. 94, 217-227. Ponnamperuma, C. (1964), Abiological synthesis of some nucleic acid con- stituents. In: S. W. Fox (Ed.) The Origins of Prebiological Systems, Academic Press, 221-242. Ponnamperuma, C., R. S. Young, E. P. Munox, and B. K. McCaw (1964), Guanine: Formation during the thermal polymerization of amino acids. Science 143, 1449-1450. Rohlfing. D. L. (1964), Catalytic activity and heat inactivation of thermal poly-a-amino acids. Ph.D. dissertation, Florida State University. Schramm, G. (1964), Synthesis of nucleosides and polynucleotides with metaphosphate esters. In: S. W. Fox (Ed.) The Origins of Prebiological Systems, Academic Press, 299-315; also, Schramm, G., H. Grotsch, and W. Pollmann (1962), Non-enzymatic synthesis of polysaccharides, nucleo- sides and nucleic acids and the origin of self-reproducing systems, Angew. Chem. Intern. Ed. Engl. I, 1-7. Schwartz, A. and S. W. Fox (1964), Thermal synthesis of internucleotide phosphodiester linkages. Biochim. Biophys. Ada 87, 694-696. Sela, M. (1962), Some contributions of the study of synthetic polypeptides to the understanding of the chemical basis of antigenicity. In: M. A. Stahmann (Ed.) Polyamino Acids, Polypeptides, and Proteins, University of Wis- consin Press, 347-358. Siegel, S. M. (1957), Catalytic and polymerization-directing properties of mineral surfaces. Proc. Nat'l. Acad. Sci. U. S. 43, 811-817. Stahmann, M. A. (1962), Chemotherapeutic possibilities of polyamino acids. In: M. A. Stahmann (Ed.) Polyamino Acids, Polypeptides, and Proteins, University of Wisconsin Press, 329-340. Steam, E. W. and A. E. Stearn (1924), The chemical mechanism of bacterial behavior. I. Behavior toward dyes—factors controlling the Gram reaction. J. Bacterial. 9, 463-477. Urey, H. C. (1961), The planets. In: L. V. Berkner and H. Odishaw (Eds.) Science in Space, McGraw-Hill Book Co., p. 204. Wald, G. (1957), The origin of optical activity. Ann. N. Y. Acad. Sci. 69, 352- 368.