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Colloque organisé par Walter Gehring et Manfred Eigen du 10 au 16 septembre 2004ParticipantsGustav Arrhenius, Steven Benner, André Brack, Christian De Duve, Manfred Eigen, Walter Gehring, Gerald Joyce, William F. Martin, Leslie Orgel, J. William Schopf, Christoph Schuster, Alan W. Schwartz, Jane Shen-Miller, Jack Szostak, Edward N. Trifonov, Ruthild Winkler-OswatitschRésuméDu 10 au 16 septembre, les participants à la conférence sur les origines de la vie ont pu profiter de la généreuse hospitalité de la Fondation des Treilles. La chaleureuse atmosphère de ce magnifique endroit associé à l’ambiance si particulière qui s’en dégage ont généré de vivants échanges très animés au sein des différents experts. Tous étaient conviés à réfléchir sur une problématique aussi vieille que la biologie et la philosophie elles mêmes: les origines de la vie. Une réelle approche interdisciplinaire de cette thématique a permis de l’envisager sous différents angles. De plus, les diverses interventions ont conduit les auditeurs jusqu’à la pointe des connaissances des disciplines scientifiques concernées.L’évolution biologique a dû être précédée d’une évolution chimique. Jusqu’à récemment un paradoxe entravait les réflexions sur les origines de la vie: on pensait que seules les protéines pouvaient catalyser la réplication des acides nucléiques, considérés comme les dépositaires du patrimoine génétique, et qu’elles seules pouvaient assurer le transfert de l’information génétique aux protéines. Ainsi, on croyait que l’existence préalable des protéines était nécessaire avant toute synthèse d’acides nucléiques mais on pensait également qu’en absence d’acides nucléiques aucune synthèse protéique ne pouvait avoir lieu. Ce point de vue a profondément été modifié par la découverte des propriétés catalytiques de certains ARN: les fameux ribozymes. De plus, de récentes études aux rayons X ont révélé que le site actif impliqué dans la formation des liaisons peptidiques (donc dans la synthèse protéique) était entièrement constitué d’ARN. Cela a conduit à la conclusion de l’existence probable d’un monde ARN bien avant que les protéines génétiquement codées ne jouent un quelconque rôle. Le problème principal de la chimie prébiotique est donc devenu celui de l’origine de l’ARN. Il est parfaitement envisageable que de petites protéines prébiotiques aient été produites à partir d’acides aminés extraterrestres, originaires du milieu interstellaire ou d’acides aminés formés dans les océans, près des sources hydrothermales sous marines, là où les premières briques de la vie ont pu être concentrées comme dans un réacteur. Même au niveau de la reproduction des molécules prébiotiques, variation et sélection, qui sont les conséquences nécessaires de leur capacités inhérentes d’autoreproduction ou de reproduction complémentaire, sont déjà les maîtres mots de l’évolution. La transition d’une évolution chimique à une évolution biologique est liée à la formation de doubles membranes lipidiques. Il a été démontré que des vésicules composées d’acides gras simples peuvent grandir et se diviser en réponse à des forces purement physiques et chimiques, indiquant qu’aucune machinerie biologique complexe n’est requise dans les processus de croissance et de division de telles vésicules. De plus, l’assemblage spontané et l’incorporation d’acides nucléiques dans des vésicules membranaires sont accélérés sur des surfaces minérales, aboutissant à la formation de vésicules proches de cellules primitives. Des études paléontologiques indiquent que les fossiles les plus agés découverts jusqu’à présent sont vieux d’au moins 3,5 milliards d’années. Ce sont des stromatolites constitués de plusieurs couches de cyanobactéries probablement déjà douées de capacités photosynthétiques. La comparaison avec des cyanobactéries actuelles suggère en effet que ces organismes les plus primitifs étaient déjà capables de détecter la lumière. Des analyses bioinformatiques suggèrent fortement que les toutes premières protéines, de courts oligopeptides de 6 ou 7 acides aminés, étaient codés par des oligonucléotides d’une longueur de 18 à 21 bases organisés en motifs d’épingle à cheveux. Des vestiges de tels motifs d’épingle à cheveux sont par ailleurs toujours détectables dans les séquences d’ADN modernes.En résumé, une approche interdisciplinaire allant de la paléontologie, à la chimie en passant par la bioinformatique permet désormais d’entrevoir de nouvelles perspectives sur les origines de la vie. Ainsi, il sera peut être possible, dans un proche futur, de reconstruire les origines physico-chimique de la vie sur Terre.ReviewThe participants of the workshop on the Origin of Life enjoyed the generous hospitality of the “Fondation des Treilles”. The warm atmosphere of this beautiful place with its unique “ambiance” led to the most lively and animated discussions among the invited experts on a problem that is as old as biology and philosophy themselves. The topic was approached from many different angels in a truly interdisciplinary fashion, and the various talks lead to the forefront of the various scientific disciplines that are concerned.The meeting covered topics of molecular evolution from physical theory through chemical models up to biological realization.The following abstracts provided by the participating authors give a good survey of the problems that were discussed.André Brack, Catalytic prebiotic peptidesExperimental data were presented to support the possible formation of prebiotic catalytic miniproteins from extraterrestrial amino acids made in the interstellar medium. Sixteen amino acids have been identified when irradiating in the laboratory ices of carbon monoxide, carbon dioxide, water, ammonia and methanol under interstellar conditions. Exposure experiments in Earth orbit onboard satellites demonstrated that amino acids can be transported safely in space by cometary grains provided a mineral protection thicker than 5 microns. Amino acids can be polymerised into short miniproteins under conditions simulating the submarine hydrothermal systems. Short miniproteins made of alternating sequences of hydrophilic and hydrophobic amino acids can be selected via the formation of stable and one-handed sheet structures. Some of these selected structures exhibit catalytic activity, thus foreshadowing the modern enzymes. New chemical approaches have been discussed aiming at improving the performances of the prebiotic catalytically active mini proteins reconstructed in the test tube.Christian de Duve, Singularities in the Origin and Evolution of LifeThe origin evolution of life involve a large number of singularities, for example, the universal genetic code of the LUCA, the last universal common ancestor of all known living beings. A number of mechanisms may theoretically account for such singularities.One mechanism is deterministic necessity, which rules chemistry. The early steps in the origin of life, being chemical in nature, were bound to take place under the conditions that prevailed.Another important mechanism is selection, which depends on environmental factors and also on inner constraints, such as genome structure or body plan. In the talk, attention was drawn to the distinction between direct or molecular, selection and indirect, or cellular, selection, and it was pointed out that the second type must have started very early, which implies that cellularization must have taken place at the latest as soon as translation started developing. Early cells cannot have freely shared their genes, as postulated by some theories. For selection to occur, they must have been capable of Darwinian competition.Selection is often mutual. Selected entities often fish out reciprocally from the environment the entities involved in their selection. Thus RNAs selected to become RNAs may have selected from the prebiotic pool, for use in protein synthesis, the amino acids with which they interacted.Selection can be optimizing. All that is needed is for the evolving systems to be able to explore the whole range of possibilities open to them (ex. sequence space, or mutational field) exhaustively or nearly exhaustively, for the variant best adapted to environmental conditions to emerge with a high degree of probability. This phenomenon may occur more frequently than is suspected. A surprising example is the genetic code, which seems to be close to optimal in minimizing the harmful consequences of point mutations.Some singularities are due simply to the extinction of other lineages without selective pressure (pseudo-bottleneck). Frozen accidents are extremely rare if they occur at all (chirality?). There is no room, or need, in the history of life, for fantastic luck or intelligent design.Conclusion: Little contingency, much necessityManfred Eigen, The Molecular Causes of LifeThe lecture reviewed the physical prerequisites for a living system, taking for granted that life started at the molecular level according to a Darwinian mechanism. For a physical theory Darwin’s criteria appear to be necessary, but they require additional conditions in order to be experimentally realisable. Reproduction, variation and selection do appear at the molecular level, where they are necessary consequences of inherent self- (or complementary) reproduction. Nucleic acids represent a class of information carrying macromolecules which provide such properties, including selection as a consequence of reproduction and variation, rather than as an independent prerequisite. Proteins as a class of molecules are devoid of inherent self-reproduction, which could occur only for particular cyclic mechanisms. An additional prerequisite is error-proneness in relation to the size and reproduction rates of the information carrying sequences, which has two consequences: selection appears to be a first order phase transition, and it stabilizes a defined mutant distribution which is the target of selection. The theoretical frame work for describing such systems has been outlined in the lecture and three model experiments were described that allowed for testing the results of the theory. In fact, “life in the test tube” is the basis for a new industry called “evolutionary biotechnology”.Walter Gehring, The Evolution of Eyes and PhotoreceptorsRecent experiments on the genetic control of eye development have opened up a completely new perspective on eye evolution. The demonstration that targeted expression of one and the same master control gene, i.e. Pax6 can induce the formation of ectopic eyes in both insects and vertebrates, necessitates a reconsideration of the dogma of a polyphyletic origin of the various eye-types in all the animal phyla. The involvement of both Pax6 and six1 and six3 genes which encode highly conserved transcription factors, in the genetic control of eye development in organisms ranging from planarians to humans, argues strongly for a monophyletic origin of the eye. Since transcription factors can control the expression of any target gene provided that it contains the appropriate gene regulatory elements, the conservation of the genetic control of eye development by Pax6 among all bilaterian animals is not due to functional constraints, but a consequence of its evolutionary history. The prototypic eyes postulated by Darwin to consist of two cells only, a photoreceptor and a pigment cell were accidentally controlled by Pax6 and the subsequent evolution of the various eye-types occurred by building onto this original genetic program. A hypothesis of intercalary evolution is proposed which assumes that the eye morphogenetic pathway is progressively modified by intercalation of genes between the master control genes on the top of the hierarchy and the structural genes like rhodopsin at the bottom. The recruitment of novel genes into the eye morphogenetic pathway can be due to at least two different genetic mechanisms, gene duplication and enhancer fusion.In tracing back the evolution of eyes further, beyond bilaterians, we find highly developped eyes in some box-jellyfish as well as in some Hydrozoans. In Hydrozoans the same orthologous six genes (six1 and six3) are required for eye regeneration as in planarians, and in the box jellyfish Tripedalia a pax B gene which may be a precursor of Pax6 was found to be expressed in the eyes. In contrast to the adults, which have highly evolved eyes, the Planula larva of Tripedalia has single- celled photoreceptors similar to some unicellular protists. For the origin of photoreceptor cells in metazoa I propose two hypotheses, one based on cellular differentiation and a more speculative one based on symbiosis. The former assumes that photoreceptor cells originated from a colonial protist in which all the cells were photosensitive and subsequent cellular differentiation to give rise to photoreceptor cells. The symbiont hypothesis, which I call the Russian doll model, assumes that photosensitivity arose first in photosynthetic cyanobacteria which were subsequently taken up into red algae as primary chloroplasts. The red algae in turn were taken up by dinoflagellates as secondary chloroplasts and in some species evolved into the most sophisticated eye organelles, as found e.g. in some dinoflagellates like Erythropsis and Warnovia which lack chloroplasts. As dinoflagellates are commonly found as symbionts in cnidarians, the dinoflagellates may have transferred their photoreceptor genes to cnidarians. In cnidarians such as Tripedalia the step from photoreceptor organelles to multicellular eyes has occurred. These two hypotheses, the cellular differentiation and the symbiont hypothesis, are not mutually exclusive and are the subject of further investigations.Gerald Joyce, The in Vitro RNA WorldIt is believed that an RNA-based genetic system, usually referred to as the “RNA world”, preceded the DNA and protein-based genetic system that has existed on Earth for the past 3.5 billion years. Questions concerning how the RNA world arose and the degree of complexity it attained can be addressed through laboratory experiments in prebiotic chemistry and RNA biochemistry.In the realm of prebiotic chemistry, one seeks to explain how the chemical components of RNA (ribose, phosphate, and nucleotide bases) arose and assembled to form polynucleotides in the presence of a complex mixture of closely related compounds. Ribose, for example, would have been accompanied by many other sugars, and is more reactive and degrades more rapidly than these other sugars. Taking advantage of the greater reactivity of ribose, we found that it reacts especially rapidly with cyanamide to form a stable bicyclic adduct. This product crystallizes spontaneously in aqueous solution, forming discrete homochiral domains. Ribosecyanamide in turn reacts with cyanoacetylene to form cytosine α-nucleoside in nearly quantitative yield.Central to the operation of the RNA world is the ability of RNA to catalyze the replication of RNA, thereby enabling RNA-based evolution. Through methods of test-tube evolution, we have developed RNA enzymes that catalyze the template-directed joining of RNA. One such enzyme contains only three of the four subunits of RNA (A, U, and G, but lacking C). This subsequently was evolved to produce a more reactive variant that contains all four subunits, as well as a less reactive variant that contains only two subunits (lacking C and G). Once Darwinian evolution begins to operate, even a highly restricted set of chemical building blocks can give rise to macromolecules with complex biochemical function.William F. Martin, FeS, thioesters, RNA, hypercycles, and chemical energy at a Hadean hydrothermal vent: A geobiochemical model for the origin of life that seems, in principle, to work in considerable detailThere are many, many problems concerning the origin of life. One of them has been termed, inter alia by C. de Duve, the “concentration problem”. In essence, it relates to the circumstance that under any scenario for the origin of life, with whatever form of prebiotic chemistry, there must be some form of concentrating mechanism that will provide sufficient chemical concentrations of the building blocks of life such that they could react with one another in order to bring forth the chemistry of living systems. It is proposed that a hydrothermal vent, or “hydrothermal reactor” could, in principle, provide a conceptional alternative solution, to the concentration problem. From that, the somewhat radical corollary follows that the last common ancestor of all cells was not free-living, but confined to the reactor instead.Leslie Orgel, Prebiotic Chemistry and the Origin of the RNA WorldRecent X-ray studies show that the active site for the synthesis at peptide bonds on the ribozome is made up entirely from RNA. This makes it almost certain that there was once an RNA world in which genetically coded proteins played no part. The principle chemical problem for prebiotic chemistry is therefore the origin of RNA. There are two possibilities: either RNA was formed de novo on the primitive earth or RNA was the invention of some simpler genetic system based on easily synthesized monomers. Arguments for and against each hypothesis were presented. Basically, it is very hard to make a molecule as complicated as RNA, but we cannot think of anything much simpler that would work.J. William Schopf, Palaeobiologic evidence of early life on EarthIn comparison with the fossil record of the Phanerozoic Eon (the most recent ~550 million years) and the Proterozoic (&#60; 2, 500-million-year-old) Precambrian, that of the Archean Eon (encompassing Precambrian Earth history earlier than 2, 500 million years ago) is minuscule — chiefly because of the paucity of such very ancient rock units that have survived to the present. Nevertheless, three independent lines of evidence from Archean rocks point to the same conclusion, namely, that Earth hosted a diverse, thriving microbial biota at least as early as 3, 500 million years ago.(1) Stromatolites — megascopic, finely layered, commonly mound-shaped mineralic (commonly carbonate) structures produced by mat-building microbial communities – are known from units dating from ~3, 490 million years ago, in the Dresser Formation of Western Australia, they occur at localities scattered over many tens of square kilometers.(2) Thousands of carbon isotopic measurements of co-existing carbonate- and organic-carbon, including hundreds from Precambrian geologic units, trace the characteristic signal of biologic photosynthesis to ~3, 500 million years ago, both in the Pilbara Craton of Western Australia and the Barberton Mountain Land of South Africa.(3) Cellularly preserved microscopic fossils have been reported from seven geologic units dated to be between 3, 300 and 3, 500 million years in age, including the Dresser Formation (~3, 490 million years old) and the slightly younger (~3, 465 million years old) Apex chert, both of Western Australia. Techniques newly developed to study individual microfossils — carbon isotopic analyses by secondary ion mass spectrometry and analyses of the chemical-structural composition, geochemical maturity, and the two- and three-dimensional distribution of the carbonaceous (kerogenous) components of such fossils by Raman spectroscopic imagery — provide important new bases by which to evaluate the biogenicity of such minute cellular fossils.Taken together, such data indicate that life’s origin must appreciably predate 3, 500 million years ago.Peter Schuster, RNA evolution, kinetic folding and molecular switchesThe evolution of RNA molecules in populations through mutation and selection is modeled in silico by means of optimization of molecular structures in the spirit of an aptamer selection experiment. Neutrality in the sense that many RNA sequences form the same secondary structure is indispensable for success and efficiency of the optimization process. The degree of neutrality is substantially larger for conventional AUGC sequences than for GC-only molecules, and hence evolutionary optimization of structures derived from GC sequences is a much harder task. A deeper explanation of this fact is obtained when the relation between sequences and structures is considered as a mapping from sequence space into a space of structures called shape space. Most of the common structures of AUGC sequences form connected neutral networks in sequence space on which populations can migrate almost everywhere, whereas the neutral networks of GC-only sequences consist of many islands that require hopping strategies with low probability events of jumping from one component to the other. The concept of sequence structure mapping makes an interesting prediction called intersection theorem when extended to suboptimal structures: For every pair of secondary structures there has to be at least one sequence that can form both conformations, commonly one as the minimum energy structure and the other one as a suboptimal structure or both as suboptimal conformations. Intersection sequences can be designed with predefined barrier heights separating them. A few experimental examples of RNA sequences with two or more (meta)stable structures are presented.Jack W. Szostak, The Transition from Chemical Evolution to Darwinian EvolutionAll modern life uses bilayer lipid membranes as the fundamental cellular boundary structure. We have been using simple model systems to ask how the first cellular structures might have replicated. We have shown that vesicles composed of simple amphiphiles such as fatty acids can grow and divide in response to purely physical and chemical forces, i.e. biological machinery is not required for growth and division. We have also found that the spontaneous assembly of such vesicles from fatty acid micelles is accelerated by the presence of mineral surfaces; moreover, specific minerals such as the clay montmorillonite may have helped bring nucleic acids into membrane vesicles – thus uniting the key components of cellular life. Vesicles that contain RNA exhibit interesting and unexpected properties. For example, we have found that competition between vesicles for membrane material can be driven by the osmotic pressure resulting from encapsulated RNA. We suggest that RNA replicating inside vesicles could have driven vesicle growth, resulting in competition at a cellular level.Edward N. Trifonov, Decipherable past of the triplet codeModern genetic sequences, of proteins and nucleic acids, carry an immense information about functions and malfunctions of millions of various species. With all complexity and volume of the sequences, they also have to contain vestiges of what they have been a long time ago, in the very beginning of life. After all, life is likely to have started with something very simple, perhaps, even astonishingly simple.With the arsenal of the sequence available for bioinformatic analysis it is not only possible to glimpse into the life’s past, but the full reconstruction of evolutionary history of the genetic code became possible. The resulting evolutionary chart is highly suggestive, and many predictions that follow from it, indeed, are confirmed. Further reconstruction of the earliest molecular evolution reveals that the earliest proteins – short oligopeptides of 6-7 amino-acid residues appear to have been encoded by 18-21 bases long oligonucleotides, folded in hairpin structures. The vestiges of the hairpins are still detectable in modern sequences, as well as further sequence and structure elements of evolving early life, to be deciphered.