The Origin of Cellular Life and Biosemiotics

Recent successes of systems biology clarified that biological functionality is multilevel. We point out that this fact makes it necessary to revise popular views about macromolecular functions and distinguish between local, physico-chemical and global, biological functions. Our analysis shows that physico-chemical functions are merely tools of biological functionality. This result sheds new light on the origin of cellular life, indicating that in evolutionary history, assignment of biological functions to cellular ingredients plays a crucial role. In this wider picture, even if aggregation of chance mutations of replicator molecules and spontaneously self-assembled proteins led to the formation of a system identical with a living cell in all physical respects but devoid of biological functions, it would remain an inanimate physical system, a pseudo-cell or a zombie-cell but not a viable cell. In the origin of life scenarios, a fundamental circularity arises, since if cells are the minimal units of life, it is apparent that assignments of cellular functions require the presence of cells and vice versa. Resolution of this dilemma requires distinguishing between physico-chemical and biological symbols as well as between physico-chemical and biological information. Our analysis of the concepts of symbol, rule and code suggests that they all rely implicitly on biological laws or principles. We show that the problem is how to establish physico-chemically arbitrary rules assigning biological functions without the presence of living organisms. We propose a solution to that problem with the help of a generalized action principle and biological harnessing of quantum uncertainties. By our proposal, biology is an autonomous science having its own fundamental principle. The biological principle ought not to be regarded as an emergent phenomenon. It can guide chemical evolution towards the biological one, progressively assigning greater complexity and functionality to macromolecules and systems of macromolecules at all levels of organization. This solution explains some perplexing facts and posits a new context for thinking about the problems of the origin of life and mind.     

Origins of Life Research: a Bibliometric Approach

This study explores the collaborative nature and interdisciplinarity of the origin(s) of life (OoL) research community. Although OoL research is one of the oldest topics in philosophy, religion, and science; to date there has been no review of the field utilizing bibliometric measures. A dataset of 5647 publications that are tagged as OoL, astrobiology, exobiology, and prebiotic chemistry is analyzed. The most prolific authors (Raulin, Ehrenfreund, McKay, Cleaves, Cockell, Lazcano, etc.), most cited scholars and their articles (Miller 1953, Gilbert 1986, Chyba & Sagan 1992, W?chtersh?user 1988, etc.), and popular journals (Origins of Life and Evolution of Biospheres and Astrobiology) for OoL research are identified. Moreover, interdisciplinary research conducted through research networks, institutions (NASA, Caltech, University of Arizona, University of Washington, CNRS, etc.), and keywords & concepts (astrobiology, life, Mars, amino acid, prebiotic chemistry, evolution, RNA) are explored.     

Transferable Measurements of Heredity in Models of the Origins of Life

We propose a metric which can be used to compute the amount of heritable variation enabled by a given dynamical system. A distribution of selection pressures is used such that each pressure selects a particular fixed point via competitive exclusion in order to determine the corresponding distribution of potential fixed points in the population dynamics. This metric accurately detects the number of species present in artificially prepared test systems, and furthermore can correctly determine the number of heritable sets in clustered transition matrix models in which there are no clearly defined genomes. Finally, we apply our metric to the GARD model and show that it accurately reproduces prior measurements of the model’s heritability.     

Cellular Life Could Have Emerged from Properties of Vesicles

It is indicated why it is plausible to assume that the initiation of cellular life was based on properties of vesicles. Vesicle properties relevant for the process of vesicle self-reproduction are revealed. Some open questions related to the idea that vesicle self-reproduction is an evolutionary process that includes the elements of the Darwinian selection are put forward, and some suggestions are made for possible directions of further research.     

The Prebiotic Leslie Orgel: Some of His Contributions to Our Understanding of the Origins of Life

In the previous recollection Jack Dunitz presented a delightful account of Leslie's pre-prebiotic life as a theoretical inorganic chemist. In this account I will present my recollections of his contributions, as a chemist-molecular biologist, to the field of origins of life.Leslie officially started his prebiotic research upon arrival at the Salk Institute in September 1964. Anna Beck and I, who arrived there at that time and Rolf Lohrmann and Robert Sanchez who joined the group within first year, were the vanguard of the large group of postdoctorals and graduate students that have spent time in Leslie's laboratory. John Sulston and Carl Woese were among the notables that spent time in Leslie's lab during his initial years at Salk.Leslie's emphasis on the new and different, which was described by Jack Dunitz, continued at Salk. He would greet me each day with well Jim, what's new! Or he would come upon an unusual reaction from the organic chemistry literature and ask me to explain it. Occasionally something new would occur in the lab and we would discuss its ramifications at great length throughout the day. He would often come up with a key suggestion on how this new finding should be extended to provide insight into an entirely different area. On other occasions he would suggest an empirical approach, such as setting up a series of reaction mixtures putting one of each of the metal salts in the lab inventory into each reaction, to determine if it was catalyzed by metal ions. This latter approach always seemed to me to be inconsistent with his background as a theoretician since I have yet to find a theoretician who would follow such a blatantly empirical approach to the discovery of new chemical reactions.Leslie claims to have no competence in the laboratory but he certainly understands what is required to obtain meaningful experimental data. First, he can often see through a forest of data and suggest a pivotal simple experiment to prove or disprove a hypothesis. Second, he has demanding standards for quality experimental design and execution. I have heard him on many occasions patiently (occasionally impatiently if it was a repeat offender) chastising a researcher in his laboratory ... for not performing the proper controls... to establish the validity of their experimental findings.Leslie started working on the prebiotic synthesis of nucleic acids and their replication when he came to Salk and was extremely successful in both studies. He improved the Oro synthesis of adenine (Oro, 1960) by extending it to dilute solutions of HCN (Ferris and Orgel, 1966) and to a general prebiotic synthesis of purines (Sanchez et al., 1966a). He also recognized that cyanoacetylene contained the carbon backbone of the pyrimidine ring and used it as a starting material for the prebiotic synthesis of pyrimidines (Sanchez et al., 1996b). Approaches to the prebiotic syntheses of nucleosides and nucleotides flowed logically from these studies (Beck et al., 1967; Lohrmann and Orgel, 1968, 1971; Fuller et al., 1972).Leslie conducted research on the nonenzymatic template-directed synthesis of RNA concurrently with studies on prebiotic synthesis. This research was initiated by the important discovery that the carbodiimide-driven condensation of A with pA gives higher yields of A²pA in the presence of poly(U) than in its absence (Sulston et al., 1968). Some minor reaction products included A³pA, A⁵pA and trimers. This discovery was followed by the substitution of an imidazole activated pA (ImpA) for the carbodiimide and pA in the reaction with A on a poly(U) template which gave much better yields of dimers and trimers (Weimann et al., 1968). In the following year this reaction was extended to the synthesis of oligo(G)s on a poly(C) template (Sulston et al., 1969), the system that was eventually shown to be optimal for probing the scope of nonenzymatic template-directed syntheses. The development of the RPC-5 column for the analysis of the oligonucleotides formed by template-directed synthesis was pivotal in characterizing the length and the regioselectivity of the phosphodiester bonds formed in these reactions (Lohrmann et al., 1980). A further advance was the development of the 2-methylimidazole activating group which resulted in the formation of oligo(G)s by template-directed synthesis that contain predominantly 3', 5'-linked phosphodiester bonds. This reaction proceeds in the solution phase (Inoue and Orgel, 1981) in contrast to the Zn²⁺- and Pb²⁺-catalyzed reactions which, while regioselective for the formation of the 3', 5'- and 2', 5'-linked phosphodiester bonds respectively, proceed via an insoluble metal complex (Lohrmann et al., 1980). Thus the 2-methylimidazole activating group made it possible to explore the efficiency of template-directed synthesis using templates containing different bases.The first self-replicating system, that was based on template-directed synthesis, was prepared by Günter von Kiedrowski in Leslie's laboratory in 1986 (von Kiedrowski, 1986). Leslie devised a replicater, which exhibited autocatalytic kinetics, that was also based on a templating reaction (Zielinski and Orgel, 1987).While prebiotic peptide synthesis was not a dominant theme in his laboratory Leslie did make important contributions to this field of work. He investigated the mechanism of peptide synthesis in aqueous solution using carbonyl diimidazole as the condensing agent (Ehler and Orgel, 1976) and he was able to make polypeptides containing 55 mers on mineral surfaces (Ferris et al., 1996). He proposed that the condensation of amino acids on the primitive Earth could have resulted in short polypeptides with alternating structures that would have formed small -sheets (Brack and Orgel, 1975). Subsequent studies have shown that some -sheets catalyze the hydrolysis of RNA (Barbier and Brack, 1992).Leslie, collaboratively with Francis Crick, has also published some theoretical papers dealing with the origin of life. The most perceptive was their anticipation of the RNA world before the name was coined by Gilbert (1986). In companion papers (Crick, 1968; Orgel, 1968), they suggested that RNA could have catalytic activity in addition to its ability to store genetic information, so that it could have been the basis for the first life. They noted that life based on protein was less likely because of its inability to preserve its sequence information by replication. In another very provocative paper they proposed that life on Earth may have been seeded here by intelligent aliens in a process they call Directed Panspermia (Crick and Orgel, 1973). They reckoned that the seeds of life might not survive the trip through open space but these initial microorganisms could have survived a trip through space if properly shielded in a spacecraft. In this scenario the Earth is a giant Petri dish and these aliens have performed an experiment using it. I have always felt that this paper had a major tongue-in-cheek component but it is often seriously mentioned as one possible explanation for the presence of life on Earth.In addition to his search for the novel and unusual Leslie also finds it challenging to search for the practical (again, not the usual practice of a theoretician!). He has the remarkable ability to appreciate the practical applications of his research and I know of at least two ideas that resulted in useful patents. (Some of the income from these patents is used to finance group parties at first rate restaurants.) One patent stemmed from the research on the prebiotic synthesis of pyrimidine nucleosides which Bob Sanchez developed into a an efficient preparation of the antileukemia agent cytosine arabinoside from cyanoacetylene, cyanamide and arabinose (Sanchez and Orgel, 1970). This successful patent is an excellent example of how the so called esoteric work in prebiotic chemistry led to a simple and new route to the synthesis of drugs or other useful materials. Another valuable patent came from the work of Barbara Chu which has been developed into a test for the genes from pathogens. She found that it was possible to prepare the 5'-imidazolides of high molecular weight QB RNA without affecting its autocatalytic replicating ability. This made it possible to attach cleavable reporter groups such as biotin or DNA probes to QB via the imidazolide intermediate, the selected DNA-QB probe could then be amplified by QB replicase, and easily detected after amplification (Chu et al., 1986).The search for useful therapeutic agents continues. In 1997 Leslie identified yet another possible application of Barbara's work. She made use of results from prebiotic chemistry showing that oligomers of glutamic acid bind irreversibly to hydroxylapatite, the predominant mineral in bone. She then attached potential therapeutic agents to the amino acid oligomers and demonstrated that they bound to the hydroxylapatite. This approach may be used to bind potential therapeutic agents to hydroxylapatite with the possibility that this might be a way to bring these agents to particular target site in bones (Chu and Orgel, 1997).The honors and awards that Leslie has received underline the high esteem in which he is held by his fellow scientists. He was recognized as a brilliant scientist by the British colleagues when he was awarded the Harrison prize of the Royal Society of Chemistry at the tender age of 30. Only five years later was he elected to the Royal Society. Among the awards he has received in the US are his election to the American Academy of Arts and Sciences in 1985, the National Academy of Sciences in 1990 and the Harold C. Urey medal of the International Society for the Study of the Origins of life in 1993. We in the field of the origins of life have not only benefitted from his major contributions to this field but the reputation of the field has also benefitted from having such a distinguished scientist as one of our own.Happy 70th birthday, Leslie! I thank you for baptizing me with HCN and sending me forth into the prebiotic world. It has been great fun as well as rewarding for me and I look forward to continuing our discussions of the origins of life for many years to come.     

The Evolutionary Origins of Hierarchy

Hierarchical organization—the recursive composition of sub-modules—is ubiquitous in biological networks, including neural, metabolic, ecological, and genetic regulatory networks, and in human-made systems, such as large organizations and the Internet. To date, most research on hierarchy in networks has been limited to quantifying this property. However, an open, important question in evolutionary biology is why hierarchical organization evolves in the first place. It has recently been shown that modularity evolves because of the presence of a cost for network connections. Here we investigate whether such connection costs also tend to cause a hierarchical organization of such modules. In computational simulations, we find that networks without a connection cost do not evolve to be hierarchical, even when the task has a hierarchical structure. However, with a connection cost, networks evolve to be both modular and hierarchical, and these networks exhibit higher overall performance and evolvability (i.e. faster adaptation to new environments). Additional analyses confirm that hierarchy independently improves adaptability after controlling for modularity. Overall, our results suggest that the same force–the cost of connections–promotes the evolution of both hierarchy and modularity, and that these properties are important drivers of network performance and adaptability. In addition to shedding light on the emergence of hierarchy across the many domains in which it appears, these findings will also accelerate future research into evolving more complex, intelligent computational brains in the fields of artificial intelligence and robotics.     

The Origins of Domesticated Cattle

The origin of domestic cattle has perplexed archaeologists for more than a century. Researchers have proposed various theories, which offer alternative spatial and chronological models for the origin and spread of domesticated cattle. One point of discussion is whether domestic cattle had a single or multiple origins; however, most authorities considered that the first steps towards cattle domestication were taken in southwest Asia and that domesticated cattle entered Europe with pastoralists migrating from this region. Domesticated taurine cattle were thought to have entered Africa in successive waves from southwest Asia, while zebu cattle migrated into Africa at a later date from Arabia and the Indian subcontinent. Analysis of mitochondrial DNA (mtDNA) shows that taurine and zebu cattle divergence before the Holocene and were probably domesticated independently. Recent mtDNA sequence data shows that African and European taurine cattle were probably domesticated independently, but that there was a process of genetic introgression between taurine and zebu cattle in Africa. Ancient DNA studies over the last 10 years suggest that Northern European aurochsens apparently contributed little or nothing to domestic cattle while Southern European aurochsens apparently made a significant input. However, Middle Eastern aurochsen, unfortunately not typed yet, are expected to be to be very similar to European breeds as well, both because archeological data suggest that the major center of domestication for European Bos taurus breeds was the Fertile Crescent (9), and also because a mtDNA sequence from a Syrian specimen dated at 8,000–9,000 years ago shows a typical European haplotype found both in modern breeds and the Italian aurochsen. Evidence seems to suggest that small to moderate levels of local gene flow from wild Bos primigenius females in selected breeds were either accepted or may be reinforced by Neolithic breeders.     

The Origins of the RNA World

The general notion of an “RNA World” is that, in the early development of life on the Earth, genetic continuity was assured by the replication of RNA and genetically encoded proteins were not involved as catalysts. There is now strong evidence indicating that an RNA World did indeed exist before DNA- and protein-based life. However, arguments regarding whether life on Earth began with RNA are more tenuous. It might be imagined that all of the components of RNA were available in some prebiotic pool, and that these components assembled into replicating, evolving polynucleotides without the prior existence of any evolved macromolecules. A thorough consideration of this “RNA-first” view of the origin of life must reconcile concerns regarding the intractable mixtures that are obtained in experiments designed to simulate the chemistry of the primitive Earth. Perhaps these concerns will eventually be resolved, and recent experimental findings provide some reason for optimism. However, the problem of the origin of the RNA World is far from being solved, and it is fruitful to consider the alternative possibility that RNA was preceded by some other replicating, evolving molecule, just as DNA and proteins were preceded by RNA.     

The Origins and Evolution of Culture

This article outlines a deductive theory that creates a new way to think about the origins and evolution of culture. It is Darwinian in the sense that it posits that novel concepts and behavior, like novel genes, appear randomly and are subject to selection on the basis of specific criteria that are established by the properties of living things. The theory permits us to hypothesize properties of the genome that generate culture and to infer the conditions under which selection would favor the origins of culture. Theoretical deductions lead to the conclusion that the organisms that create culture actively participate in the creation of descendants who exhibit increasing cultural abilities and who generate increases in productivity and more reliable flows of resources. Culture is not something that has evolved solely and relatively recently in the hominid line of evolution. Fossil evidence suggests that culture may have existed at least 50 million years ago, and may have originated more than 200 million years ago.     

Cellular Origins of Cyclic GMP Responses to Excitatory Amino Acid Receptor Agonists in Rat Cerebellum In Vitro

Incubated slices and freshly dissociated cells from 8-day-old rat cerebellum were used to try to identify the cells that participate in the large increases in cyclic GMP levels that follow activation of excitatory amino acid receptors in this tissue. In the slices, cyclic GMP responses to L-glutamate and related excitants were unaffected by tetrodotoxin and could be replicated by the guanylate cyclase activator nitroprusside. Nitroprusside and the receptor agonists appeared to activate the same pool of the enzyme. Prior destruction of neuroblasts, deep nuclei, or Golgi neurones did not cause loss of responses to L-glutamate. If granule cells were rendered necrotic, however, the cyclic GMP responses to all excitants tested were reduced by greater than or equal to 90%. Substantial losses of responses to veratridine and high K+ levels also occurred, but the nitroprusside-induced elevations were unaffected. In dissociated cell suspensions, the magnitude of responses to receptor agonists, but not those to nitroprusside, was markedly dependent on cell concentration. Responses to L-glutamate were the same in cell suspensions that were Purkinje cell depleted and Purkinje cell enriched. It is concluded that granule cells are primarily involved in the cyclic GMP responses to excitatory amino acids but that the cyclic GMP accumulations occur elsewhere, probably in glial cells.     

The Cultural Origins of Human Cognition.

The Cultural Origins of Human Cognition. Michael Tomasello. Cambridge, MA: Harvard University Press, 2000. 248 pp.