venerdì 8 giugno 2012

THE RNA WORLD. Between Dogma and Ideology, the risk of a genetic fundamentalism.

It seems that a Chinese mandarin spent all his life thinking, but without result, if it was the egg or the hen which preceded.
In the xx century the testimony passed into biophysics, which assumed it as an efficient metaphor of a tricky problem linked to the origin of life.
As already exposed in previous articles, in all living organisms the nucleic acids are the deposits of genetic information, whereas the proteins (enzymes) have the task of controlling the metabolic reactions. These substances must have been present since the dawning of life, without these substances life could not have had its origin. Nucleic acids and proteins, apart from the fact that they have big and complex molecules, are also dependent one of another, in the sense that the nucleic acids contain the instructions for the assembling of the proteins, but it is the proteins which operate the synthesis of the nucleic acids.
The ones need the others.
The theory of Oparin-Handane postulated that life had had its origin in a primordial broth. It is however extremely improbable that these macromolecules had a simultaneous origin in an independent way and that meeting casually they started interacting.
Hence the problem manifests itself: were the proteins to appear first or the nucleic acids? Or, to use the  now well-known and efficient metaphor of Biophysics: The problem of the egg and the hen. Was it first the egg to appear, that is the nucleic acids; or the hen, that is the proteins. Now, experiments made by Miller and other researchers in the `50’s and `60’s have made it evident that the amino acids, which form the proteins, are easy to synthesize in a prebiotic environment. Whereas, the components of the nucleic acids, that is sugars and nucleobases, are very difficult to synthesize. It was hence logical to think that the proteins were the first to appear. When, at the end of the `60’s, became evident the failure of the synthesis of proteins in the prebiotic broth, researchers began taking an interest in the nucleic acids.
It was in those years that the idea of the “RNA world” was being born.

Between the two nucleic acids, DNA and RNA, the RNA was preferred because less complex, it participates in the construction of the proteins, and in some virus it substitutes the DNA as genetic material. The original idea was that, in the primordial broth, molecules of RNA appeared first with the two functions in one: containing the genetic information, and having the function of enzymes catalyzing their own synthesis, that is being egg and hen at the same time.
Some discoveries gave a great impulse to this idea. From 1967 on, a few experiments using nucleotides activated artificially and Qß, a very complex biological enzyme, were conducted by Sol Spiegelman, Manfred Sumper and others. From such experiments were obtained RNA molecules ex novo with a different composition and dependent on the experimental conditions.
In the same period L. Orgel succeeded in obtaining, in not prebiotic conditions, short RNA molecules using nucleotides of a single nucleobase, in the presence of a matrix formed of macromolecules of the complementary nucleotide. He succeeded in obtaining, always in not prebiotic conditions, also short RNA molecules using concentrated solutions of nucleotides and salts. Now these discoveries, though of great scientific interest, gave some indication, but they did not succeed in demonstrating the self-reproducing of the RNA.
The RNA do not act as enzymes to reproduce themselves
A second discovery seemed to be able to resolve the problem. In 1983 were discovered the Ribozymes, that is RNA molecules with enzyme capacities. In that period, the enthusiasm of researchers was great; it was thought that finally the key of the mystery had been found. But in the following years it became clear that the Ribozyme have weak enzymatic properties, but above all they are not self-reproducing. It was then thought that in the prebiotic period a population of RNA molecules and a pool of enzymes were originated, perhaps particular Ribozymes. To this whole Walter Gilbert, Nobel prize for his study on DNA, gave the definition of “RNA World”. Yet, the original idea of finding RNA molecules self-reproducing (that is that had the functions of egg and hen simultaneously) had failed and, to the proteinous

enzymes, were substituted only enzymes to be discovered in the future. To be precise, the problem of egg and hen, out of the door comes back in the window.
But the problems of the RNA world are in reality much more serious.
But the problems of the RNA world are in reality much more serious.
Just to begin there does not exist, until today, any credible idea of how the RNA should have appeared in the prebiotic era. After twenty years from the beginning
of the idea of the “RNA World”, this problem was already made clear by Manfred Eigen. In “Gradini verso la vita”, 1992, in ch.8 with the title: ” In what natural conditions can life appear” he writes: «The research of a catalyzer of the synthesis of the RNA and that is of a prebiotic polymerase, probably constitutes one of the most crucial points between those pointed out in the epigraph of this chapter». After another 20 years the problem presents itself again. And Christian De Duve in “Alle origini della vita” (2008) adds: «In spite of all those efforts, the tentatives to reproduce the synthesis of the RNA in prebiotic conditions have had only limited success. The researchers have assembled short chains like the RNA through mineral catalyzers, for the most argil, with nucleotides artificially activated as precursors, and with some chosen matrix. The natural precursors, however, showed themselves less efficient, and their synthesis in plausible conditions has until now frustrated the ingenious of the researchers».
And so from twenty years to another twenty years, after half a century we are still at the point of departure.
If we go on like this, in 2065, some young researcher will write that the “RNA Word” is still seeking an enzyme for the synthesis of the RNA, and surely…we shall not be embittered not to be able to read him.
Moreover, no-one succeeded in ever obtaining the components of the RNA in prebiotic conditions. Some researches done at the beginning of the ‘60’s, of scarce interest, are continually reproposed with some variation to try to render them more credible. In the essay “Prebiotic chemistry and the origin of life” an entire chapter was dedicated to the “RNA World”, where are amply illustrated the enormous difficulties of synthesis and of selection of the fundamental molecules (Ribose and nucleobases), of the corresponding nucleotides and of the RNA. In this essay has been exposed also the opinion of authoritative scientists on this subject.
Graham Cairns-Smith has analyzed the laboratory procedure to obtain activated nucleotides and has counted 140 events (to pour, to mix, to allow to settle, to distill, etc) which should have happened in the appropriate manner; that is, like throwing a dice and obtaining number 6 for 140 times following. Hence to the enormous chemical difficulties are added just as enormous difficulties of procedure.
To conclude, except for a miracle, a “RNA World” in the prebiotic era, never existed.
Around the beginning of the ‘90’s many scientists had already become conscious of the enormous difficulties. Even some scientists who had contributed to the idea of the “RNA World” began to express their skepticism. But the expectations were many and well synthesized by C. De Duve, who although being a sustainer of the RNA World, with the intellectual honesty which is typical of him, concerning the discovery of the Ribozymes and the definition of Gilbert on the “RNA World” writes ( work already quoted): «[…] “molecules of the RNA World and cofactors [were] a set of enzymes sufficient to execute all the chemical reactions necessary for the first cellular structures”,(Gilbert 1986). Only a little word -all- transformed an important discovery into a powerful hypothesis which inflamed the imagination of scientists, galvanized efforts of research and created passion in a surprising way, on which historians and sociologists of future science will have much on which to ponder. Today the RNA model has been divulgated to such a point that its hypothetical nature tends to be almost forgotten. As a testimony the following assertion which is only one of the many of the same orientation can be made: “Before the emergence of the biological codification, the hypothetic “RNA World”, in which a single biopolymer operated both as genetic information and as phenotype functioning metabolically, forms one of the models best confirmed for the beginning of the evolution of life”(Freeland and others, 2003)».
But then, how was it possible that a theory of exclusively hypothetical nature was divulgated at such a point to be presented as confirmed?
And then, must we rally wait historians and sociologists of the future?
History goes back a long time, we must go back in time more than half a century ago.
At the beginning of the ‘50’s was discovered, by F. Crick and J. Watson, the structure with double helix of the DNA and for this discovery they received the Nobel Prize. Very soon it was discovered also that, in all living organisms, the genetic information contained in the DNA is transcribed in RNA and translated in proteins.
                                      DNA       RNA       Proteins

The opposite translation from proteins to nucleic acids does not occur. This unilateral procedure of the information, in 1957, was defined by F. Crick “The Central Dogma of biology”. It was from this “central dogma” that was created, in many researchers, the idea that, in the prebiotic era, the RNA had its origin before the proteins. As time passed, for the sustainers of the “RNA World”, stimulated by the idea that life had its origin from RNA self-reproducing molecules, the indications of experiments by Spiegelman, Sumper and Orgel became certitudes. So with reference to these experiments, Manfred affirms, (Le Scienze, June 1981): «The fundamental conclusion of these studies is that the self-reproducing of RNA systems in vitro takes place effectively also without the intervention of sophisticated enzymes. It is possible to proceed considering the evolutive consequences of the self-reproducing of the RNA without preoccupying oneself if this really took place in prebiotic times: however it did happen».
And the non-prebiotic conditions of Orgel’s experiments became, for J. E. Darnell Jr., plausible conditions: «Some recent studies on RNA chemistry confirm with vigor the idea that RNA must have existed first. L. Orgel with collaborators of the Salk Institute have demonstrated that the chain synthesis oligo-nucleotides of RNA happens spontaneously in an environment characterized by elevated concentrations of nucleotides and salts; probably such an environment had dominated on the primitive earth». (Le Scienze, December 1985). But Manfred Eigen, with reference to the above experiments, in the same article continues, «The uniformity of the products synthesized ex novo shows itself to be a consequence of natural selection and not of detailed instructions given by the self-reproducing enzyme. The central dogma is saved, at least in its general lines».
The leap has been made; the “central dogma”, thought of for living organisms, is extended to the prebiotic molecules. Genetics, which already with Neo-Darwinism had confirmed in its general lines Darwin’s theory, becoming central for biology, now becomes universal and includes everything: life, its origin, its evolution. And meanwhile a dogma enters and makes part of the research on the origin of life, with the risk of a genetic fundamentalism. Towards the beginning of ‘90’s, when the theory of “RNA World” was starting to lose part of its credit, molecular genetics explodes, that is the study of DNA and RNA. Also the “Genome Project”, that is the study of the human DNA, begins. Genetics extends itself in all the laboratories of the world with important finances and great hopes in the field of medicine, it passes from one success to another winning one Nobel Prize after another. Form Crick to Manfred Eigen, Cech and Altman, Gilbert, Szostak, all winners of the Nobel prize and, as the greater part of the geneticists, sustainers of the “RNA world”. Now it is clear that genetic research is also more credible, if one admits also the hypothesis that life had had its origin from primordial genes, and hence by controlling genes one controls life. Hence the results of some research, of limited interest for the origin of life, were emphasized by the sustainers of the theory. Slowly the idea whose nature is exclusively hypothetical, becomes dominant, it conquers reviews and newspapers, all speak of the “RNA World” and it becomes the confirmed theory; desires slowly become reality.
But Manfred Eigen also gave an official stimulus to the evolutionists, concluding in the same article (Le Scienze, June 1981):«That which is important here is what these experiments reveal on the Darwinian processes. The natural selection and evolution, which are the consequences of self-reproduction, operate at the level of the molecules in the same way at the level of cells or of species».
At a stroke Darwin’s theory is extended to molecules and hence to the origin of life.
The ideas expressed by Eigen were already known around the middle of ‘70’s and naturally the evolutionists did not let go of the occasion. Already in “The theory of evolution”, 1975, John Maynard Smith, after having given as a definition of “living”, entities which have the property of multiplication, of hereditary capacities, and of variability, concludes that the first living organisms were molecules of polynucleotides capable of doubling themselves. To sustain the capacity of doubling themselves of such molecules, he recalls the experiments of Orgel.
These were also the years of “Case and necessity” by Jacques Monod. The casual origin of life was the subject of an ample debate and was accepted by many scientists.
Richard Dawkins, one of the most authoritative evolutionists, in “The selfish gene”, 1976, explains that survival is stability and that natural selection began with the casual appearance, in the prebiotic broth, of stable molecules. But one of these molecules was self-reproducing, that is capable of producing copies of itself. During the process of copying however, there appear some errors and that permitted evolution. To resume, the self-reproducing molecules were the progenitors of life and our far ancestors. After 10 years, in 1986, Dawkins publishes “The blind watchmaker”. But in these years, case as unique event for the origin of life, begins to show its limits. In the same period is published the theory of genetic information contained in the crystal of Graham Cairns-Smith. In his new book, Dawkins abandons the idea of the casual synthesis of self-reproducing molecules in the prebiotic broth and privileges the theory of the argil crystals of Cairns-Smith, on whose surface the first self-reproducing molecules would have synthesized. Now, after an initial interest of the scientific community, the theory of Cairns-Smith lost strength. At that time was published, by Manfred Eigen “Gradini verso la vita”. According to Eigen, life had its origin through a population self-reproducing of molecules of nucleic acid through a process of functional optimization and a cycle auto-catalyst (hyper cycle). In 1989 was published by Dawkins, the third edition of “The selfish gene”. For what concerns the origin of life, Dawkins confirms, also in this edition, the theory of the casual origin of the self-reproducing molecules in the prebiotic broth, but he adds a note: «Many theories exist on the origin of life […], in this book I have chosen just one to illustrate the general idea. […]. In reality, in “ The blind watchmaker”, I have chosen deliberately another for the same reason, the theory of argil by Graham Cairns-Smith. If I wrote another book I should probably have to take the opportunity to try to explain yet another point of view, that of the German mathematician and chemist Manfred Eigen and his colleagues. That which I always seek to transmit is the idea of the fundamental properties which must be at the base of whatever good theory on the origin of life on some planet, above all the idea of genetic entities which are self-reproducing».
To conclude a theory is good only if it incorporates the idea of a self-reproducing molecule.
And so ideology enters to make part of the research on the origin of life.
Darwin’s theory of evolution, thought for superior organisms, and extended to micro-organisms is extended to molecules and so becomes universal: life, its origins, its evolution; the geneticists fuse with evolutionists. The theory of the “RNA world” is, still today, the dominant theory. And yet it is enough to read “Prebiotic Chemistry and the Origin of the RNA World” by Leslie E. Orgel (Critical Reviews in Biochemistry and Molecular Biology, 39:99–123, 2004), or “Alle origini della vita” by C. De Duve to realize that this theory after half a century, in spite of the engagement of the most brilliant chemists and biochemists in the world, has not made any steps forward. And the research on the origin, enfolded in a suffocating dogma is at a stop at Miller’s experiment.
And meanwhile the theory of the “RNA World” continues to be divulgated but, between dogma and ideology, it is in reality the theory of an inexistent world.


                                                                                                  Giovanni Occhipinti

Translated by Silvia Occhipinti: 01.02 2013
To know more:
Prebiotic chemistry and origin of life
ISBN  978-88-488-1152-1


Nessun commento:

Posta un commento