Marcello Barbieri

Scientific Autobiography

From ribosome crystals to ribotype
I graduated in 1964 at the Faculty of Science of Bologna University, and in 1965 was employed by the Faculty of Medicine of the same University as a researcher in molecular biology and a teacher of biophysics for medical students. In 1968 I discovered how to isolate ribosome microcrystals induced in chick embryos by hypothermia, and in 1970 Max Perutz invited me to spend a semester at the MRC in Cambridge (UK), where I had discussions with Francis Crick, Hugh Huxley and Aaron Klug.
In 1971, EMI announced the first scanner for computerized tomography and I became interested in the algorithms for the reconstruction of structures from projections, because they seemed to provide new models for the simulation of embryonic development. In 1972 and in 1974 I spent two semesters at the NIH in Bethesda (USA), and discovered that structures can be reconstructed from incomplete information provided that the reconstructions are performed with iterative methods that use memory matrices and codes. That brought me to the conclusion that organic memories and organic codes are essential features of embryonic development. In the meantime, the research on ribosome crystallization was going on, and from 1975 to 1980 I worked on that problem at the Max-Plack-Institute für Molekulare Genetik in Berlin. There I discovered that the formation of ribosome microcrystals in chick embryos was mainly due to biological factors rather than physical ones. More precisely, it was due to the fact that any damage to the ribosome transport system was halting the transport in some places of the cell only, and it was the accumulation of ribosomes in those small regions that induced them to form crystals. The crucial point, however, was that the whole process was dependent on the stage of embryonic development, which convinced me that the differentiation of the ribonucleoprotein system is a prerequisite for the differentiation of the whole cell. That, in turn, raised an evolutionary problem, and I concluded that the evolution of the ribonucleoprotein system of the cell – the ribotype – has been instrumental to the evolution of both genotype and phenotye.
That idea appeared in 1981 in the Journal of Theoretical Biology, together with the concept that the cell is not a genotype-phenotype duality but a trinity of genotype, phenotype and ribotype. The cell, in other words, is not a biological computer made of software and hardware, but a semiotic system made of software, hardware and codeware, i.e., a system whose code is produced by the system itself, not by an outside agent.

The Organic Codes
The genetic code is at the heart of life, but it is not the only code that exists in Nature. Any organic code is a set of rules of correspondence between two independent worlds, and requires molecular structures that act like adaptors, i.e., that perform two independent recognition processes. The adaptors are required because there is no necessary link between the two worlds, and a set of rules is required in order to guarantee the specificity of the correspondence. The adaptors, in short, are necessary in all organic codes. They are the molecular fingerprints of the codes, and their presence in a biological process is a sure sign that that process is based on a code. In splicing and in signal transduction, for example, I have shown (in 1998 and 2003) that there are true adaptors at work, and that means that those processes are based on splicing codes and on signal transduction codes. In a similar way I have shown that the presence of adaptors reveals the existence of cytoskeleton codes and of compartment codes.
Many other organic codes have been discovered within the last twenty years. Among them, the Sequence Codes (Trifonov), the Adhesive Code (Redies and Takeichi), the Sugar Code (Gabius), the Histone Code (Strahl and Allis; Turner), the Neural Transcription Codes (Jessell; Flames et al.), a Nuclear Receptors Combinatorial Code (Perissi and Rosenfeld), an Acetylation Code (Knights et al.), an Estrogen Receptor Code (Leader et al.). The definition of code has been somewhat different from case to case but this is fairly usual in biology and does not prevent us from realizing that the living world is literally teeming with organic codes.
This conclusion has extraordinary consequences for biology, because it changes not only our description but also our interpretation of the history of life. Any time that a new organic code came into being, something totally new appeared in Nature, something that had never existed before.
The origin of the genetic code, for example, made it possible to produce proteins with specific sequences and to pass them on indefinitely to other systems. That gave origin to biological specificity, the most fundamental of life’s properties. The signal transduction codes allowed primitive systems to produce their own signals and to separate their internal space from the outside environment. That was a precondition for the origin of individuality, and in particular for the origin of the cell. The splicing codes required a separation in time between transcription and translation that was a precondition for their separation in space, i.e., for the origin of the nucleus, the defining feature of all eukaryotes. The cytoskeleton codes allowed the cells to build their own scaffoldings, to change their own shapes and to perform their own movements. The origin of embryos was also associated with organic codes because typical embryonic processes like cell determination, cell adhesion, cell migration and cell death have all the qualifying features of adaptor-based codified phenomena.
The major events in the history of life, in short, went hand in hand with the appearance of new organic codes, from the first cells all the way up to multicellular life, and this suggests a very deep link between codes and evolution. It suggests that the great events of macroevolution were made possible by the appearance of new organic codes. This is the main message of the book that I wrote in 2003 (The Organic Codes) and of the book that I edited in 2008 (The Codes of Life).

The two mechanisms of evolution
The great debate on evolution culminated, in the 1930s and 40s, with the Modern Synthesis, the theoretical framework where natural selection is regarded as virtually the sole mechanism of evolutionary change.
Natural selection is due to chance variations in the hereditary characters, and is based therefore on the mechanism of molecular copying, because it is the copying of genes that leads to heredity. When a process of copying is repeated indefinitely, however, another phenomenon comes into being. Copying mistakes become inevitable, and in a world of limited resources not all changes can be implemented, which means that a process of selection is bound to take place. Molecular copying, in short, leads to heredity, and the indefinite repetition of molecular copying in a world of limited resources leads to natural selection. That is how natural selection came into existence. Molecular copying started it and molecular copying has perpetuated it ever since. This means that natural selection would be the sole mechanism of evolution if molecular copying were the sole basic mechanism of life.
The discovery of the genetic code, however, has proved that there are two distinct molecular mechanisms at the basis of life, copying and coding. The discovery of other organic codes, furthermore, allows us to generalize this conclusion because it proves that coding is not limited to protein synthesis. Copying and coding, in other words, are distinct molecular mechanisms and this suggests that they give origin to two distinct mechanisms of evolution because an evolutionary mechanism is but the long-term result of a molecular mechanism. More precisely, copying leads, in the long run, to natural selection and coding to natural conventions.
There are three major differences between copying and coding: (1) copying can only produce relative novelties whereas coding brings absolute novelties into existence, (2) copying acts on individual objects whereas coding acts on collective sets of objects, and (3) copying is about biological information whereas coding is about biological meaning. Copying and coding are profoundly different mechanisms of molecular change, and this means that they gave origin to two distinct mechanisms of evolutionary change.
Evolution, in short, took place by natural selection and by natural conventions. This is the main message of the books that I wrote in 1985 (The Semantic Theory of Evolution) and in 2003 (The Organic Codes), and it is by no way a belittlement of natural selection. It is only an extension of it, a generalization that becomes inevitable when we realize that there are two distinct molecular mechanisms at the basis of life.
In 1981, I sent the first draft of The Semantic Theory to Karl Popper, and the two handwritten letters that I received are still one of my most precious possessions. He wrote “A marvellous book…the presentation is simply beautiful…the theory is revolutionary”. These words were a great comfort and allowed me to bear for many years the indifference of the scientific community to the semantic dimension of life.

Biosemiotics
In May 2001, Thomas Sebeok invited me to review a Special Issue of Semiotica that was dedicated to celebrating the coming of age of biosemiotics – the study of signs in living systems – by celebrating Jakob von Uexküll as the chief architect of the new discipline. I accepted with enthusiasm, and I acknowledged that the two main points of the Special Issue – the making of biosemiotics and the recovery of Jakob von Uexküll from oblivion – came out with clarity and force, and were definitely a success. There was however a third point that I did not agree with. It was the idea that biosemiotics has been the crowning achievement of the tradition that goes back to Goethe, Saint-Hilaire, von Baer, d’Arcy Thompson and Driesch, a tradition that has been the historical antagonist of the ‘mechanistic’ approach of Galileo, Newton, Lamarck, Darwin and Mendel. I argued that the project of introducing meaning in biology is sacrosanct, but neo-vitalism is not the best approach. The existence of organic codes and organic meaning in nature are scientific problems that can and should be investigated with the classical method of science, i.e., with the mechanistic approach of model building.
I sent my review to Sebeok in August 2001, saying that I had not been able to write an impartial report and therefore that I would not be surprised if he turned it down. Sebeok, however, accepted it, and that convinced me that he wanted to send a message to the biosemiotic community. It was an implicit message, of course, but to me it was something like this: neo-vitalism is not forbidden in biosemiotics, but it is not compulsory. A good, old-fashioned mechanistic approach to the problem of meaning could not be ruled out, and people who were proposing it should be listened to.
Sebeok died a few months later, on December 21, 2001, and that implicit message was probably his last contribution to biosemiotics. Personally, I took it as an invitation to join the biosemiotic community and to argue in favour of a mechanistic approach to the problem of meaning from within that community. I decided to give it a try and asked to take part in the second Gathering in Biosemiotics that was going to take place in Tartu, Estonia, in June 2002. Since then I have been to all subsequent Gatherings and I have never regretted it, even if my scientific mechanism was politely ignored. To me, however, that did not matter. The important point was that the problems of biosemiotics were being discussed without the constraint of ideological principles. Gone were the triumphal tones and the neo-vitalistic declarations of the Special Issue. The reality was the feeling that nothing had been settled yet, that everything was on the move, that the exploration of the new continent of meaning had just begun.
The decisive change came in 2004, at the fourth Gathering organized by Anton Markoš in Prague. Jesper Hoffmeyer, Claus Emmeche, Kalevi Kull, Anton Markoš and myself decided that what was uniting us – the introduction of meaning in biology – was far more important than our divisions, and we should make that visible. Up until then, I had been referring to the science of biological meaning as semantic biology or biosemantics, whereas Markoš had been calling it biohermeneuthics, but we accepted to give up those favourite names of ours and to adopt the term biosemiotics that Sebeok had been campaigning for with so much passion and vigour.
We also decided to make the problem of meaning visible by producing a new Journal specifically dedicated to biosemiotics. That, in my opinion, is when biosemiotics came of age. It happened when people decided to work together not because they had the same ideas but because they accepted to put their differences aside in the interest of a greater goal.

A Journal and a Book Series
In 2004 I started looking for a publisher of a Journal or a Book Series in Biosemiotics, and came up against a whole nest of problems. What was the potential of the new field? How many people were involved in it? Was there any guarantee of continuity? How could a market research be conducted?
Experimental discoveries spread like fire, but new theories are extremely slow to take hold, because academics usually do not change their mind. Only young people have that gift, so we had to resign ourselves and work for another generation. But could a publisher accept that? Were there companies prepared to finance a project for the future? I became painfully aware that we were threading on thin ice, but then the unexpected happened.
In 2005 Springer passed on the evaluation of my proposal to a young manager by the name of Catherine Cotton, and I brace myself for another round of marketing questions. But what I got was totally different. She wanted to know what Biosemiotics was about, and started enquiring about the ideas, not about their commercial fallout. She came to our Gatherings, listened to our speeches, took notes and asked me to reply to the objections of her referees. In the end she asked me to start with neither a Journal nor a Book Series, but with a single book. That’s how Introduction to Biosemiotics came into being, at the beginning of 2007. After that first step, Springer offered me to be the editor of a Book Series, and then of a proper Journal, both of which made their first appearance in 2008.
Biosemiotics is the science of the codes of life and is potentially applicable to all fields of biology. The fact that today is only a small niche is true, but is ultimately irrelevant. The important point is that the small niche exists, that it is growing roots, that it is attracting new people every year. The organic codes exist and are bound therefore to be discovered and accepted by everybody. That is what really counts, in the long run
.

Marcello Barbieri

Ferrara, 30 January 2009