From ribosome microcrystals to ribotype
I graduated in 1964 at the Science Faculty of Bologna University and in 1965 was employed by the Medical Faculty of the same University as a researcher in molecular biology and teacher of biophysics for medical students. In 1968 I discovered how to isolate ribosome microcrystals induced in chick embryos, 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 simulating the increase in complexity that takes place in embryonic development. In 1972 and in 1974 I spent two semesters at 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 memories and codes. That convinced me that organic memories and organic codes are essential features in embryonic development.
From 1975 to 1980 I conducted further research on ribosome crystallization at the Max-Plack-Institute für Molekulare Genetik in Berlin. There I discovered that the formation of ribosome microcrystals in chick embryos was 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 movements in some regions of the cell, and it was the accumulation of ribosomes in those restricted spaces that was inducing them to form microcrystals. By exploiting this finding I was able to obtain the largest microcrystals of eukaryotic ribosomes that have ever appeared in the scientific literature (see “A Gallery of Ribosome Microcrystals” in this website).
The crucial point was that ribosome crystallization could be induced only in embryonic development and was steadily diminishing in increasingly differentiated cells, which convinced me that the differentiation of the ribonucleoprotein system is a key step in the differentiation of the cell. That, in turn, raised an evolutionary problem, and I concluded that the evolution of the ribonucleoprotein system – that I called ribotype – has been instrumental to the evolution of both genotype and phenotye.
That idea appeared in the Journal of Theoretical Biology (Barbieri 1981) 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 system made of software, hardware and codeware, i.e., a system where the codemaker is not an outside agent (as in computers) but an integral part of the system itself (as in the brain).
The Organic Codes
The genetic code is at the centre of life but it is not the only code that exists in living systems. Any organic code is a mapping 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 connection between two independent worlds, and a set of rules is required in order to guarantee the specificity of the connection. The adaptors, in short, are essential 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 2003) that there are true adaptors at work, and that means that those processes are based on splicing codes and on signal transduction codes.
Many other organic codes have been discovered. Among them, the sequence codes (Trifonov 1987, 1989, 1999), the adhesive code (Redies and Takeichi 1996; Shapiro and Colman 1999), the splicing codes (Barbieri 2003; Fu 2004; Matlin et al. 2005; Pertea et al. 2007; Wang and Burge 2008; Barash et al. 2010; Dhir et al. 2010), the signal transduction codes (Barbieri 2003), the histone code (Strahl and Allis 2000; Jenuwein and Allis 2001; Turner 2000, 2002, 2007; Kühn and Hofmeyr 2014), the sugar code (Gabius 2000, 2009), the compartment codes (Barbieri 2003), the cytoskeleton codes (Barbieri 2003; Gimona 2008), the tubulin code (Verhey and Gaertig 2007), the nuclear signalling code (Maraldi 2008), the apoptosis code (Basañez and Hardwick 2008; Füllgrabe et al. 2010), the ubiquitin code (Komander and Rape 2012), the bioelectric code (Tseng and Levin 2013; Levin 2014), the glycomic code (Buckeridge and De Souza 2014) and the acoustic codes (Farina and Pieretti 2014).
These discoveries have extraordinary consequences because they change our reconstruction and our understanding 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 gave origin to biological specificity, the most fundamental of life’s properties. The signal transduction codes allowed primitive system to interact with the environment in a reproducible way, a step that was crucial to the origin of the first modern cells. 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 scaffoldings, to change their shapes and to perform movements, including those of mitosis and meiosis. 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 characteristics that reveal the existence of coding rules.
New organic codes, in short, appeared throughout the history of life, from the first cells to multicellular creatures, and this suggests a deep link between codes and evolution. It suggests that the great events of macroevolution went hand in hand with the appearance of new organic codes. This is the main message of the books that I wrote in 1985 (The Semantic Theory of Evolution), in 2003 (The Organic Codes) and in 2015 (Code Biology: A New Science of Life).
In March 2001 I sent to Thomas Sebeok the draft of ‘The Organic Codes’, a manuscript where I pointed out that there are many organic codes in Nature and that their appearance in the history of life was associated with the great events of macroevolution. I also argued that the existence of the organic codes requires that we introduce in biology not only the concept of organic information but also the concept of organic meaning.
Sebeok kindly acknowledged the manuscript and two months later invited me to review a special issue of Semiotica edited by Kalevi Kull and entitled ‘Jakob von Uexküll: A paradigm for biology and semiotics’ (Kull 2001). I accepted with enthusiasm but soon became aware of a sharp contrast between our positions. In my book I had stressed that organic meaning comes from coding, whereas all contributors to the special issue were endorsing the Peircean view that meaning is always produced by a process of interpretation and cannot be reconciled with mechanism.
The endorsement of a non-mechanistic approach to life was indeed a constant theme of the special issue, and biosemiotics was portrayed as the crowning achievement of the idealistic tradition that goes back to Goethe, von Baer, Driesch and von Uexküll. I argued instead that 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 Thomas Sebeok in August 2001 saying that I had not been able to write an impartial report and that I would not be surprised if he turned it down. Surprisingly, however, Sebeok accepted it and I received a copyright transfer form to fill in. That gave me the idea to test his determination so I answered that I needed to keep the copyright to myself for a forthcoming book. Since he had been taken ill, it was his wife Jean who replied and wrote “he has made some rare exceptions to the copyright rule when necessary, and he would be willing to do so in this case”. That convinced me that Sebeok wanted to publish the review, and this meant that in principle he was not against a mechanistic approach to the problem of meaning.
Sebeok died a few months later, on December 21, 2001, and my review appeared in Semiotica in the following year (Barbieri 2002). Personally, I took it as an invitation to join the biosemiotic community and to argue in favour of a mechanistic approach from within that community. I decided therefore 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. There I found a genuine attention to novel ideas and a willingness to discussing them without the constraint of ideological principles. I had the same impression a year later, at the third Gathering, and realized that a dialogue could start between us over the problem of meaning in nature. At the same time, I became aware that our discussions were not enough. We needed to reach out to a larger audience and that is why, in March 2004, I proposed to create a new journal specifically dedicated to biosemiotics.
The agreement was reached in June 2004, at the fourth Gathering organized by Anton Markoš in Prague. Jesper Hoffmeyer, Claus Emmeche, Kalevi Kull, Anton Markoš and myself met in a pub and decided that what was uniting us – the introduction of meaning in biology – was far more important than our divisions. Up until then, I had been referring to the study of biological meaning as semantic biology, whereas Markoš was 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.
The practicalities of looking for a publisher, testing the market and collecting a critical mass of papers took a few years, but eventually I signed a contract with Springer as editor-in-chief of Biosemiotics and the journal started publishing in 2008. My editorial position, on the other hand, was not preventing me from developing the scientific approach to the problem of meaning, and this started a debate that eventually led to a parting of the ways.
Two types of semiosis
Biosemiotics is the idea that semiosis (the production of signs) is such a fundamental component of life that one cannot exist without the other. But where does semiosis come from? On this point, biosemiotics has been traditionally split into two opposite camps that represent its two historical starting points.
The synthesis of biology and semiotics that today we call biosemiotics was developed independently in two fields that lie at the opposite ends of academia. The first origin took place in molecular biology as a result of the discovery of the genetic code (the name molecular biosemiotics was coined by Marcel Florkin, in 1974, precisely to designate the study of semiosis at the molecular level). The second origin took place in the humanities and was masterminded by Thomas Sebeok in two distinct stages. In 1963, Sebeok extended semiosis from human culture to all animals and founded the new research field of zoosemiotics (Sebeok 1963). More than 20 years later, he made a second extension from animals to all living creatures and called it biosemiotics (Anderson et al. 1984, Sebeok and Umiker-Sebeok 1992, Sebeok 2001).
Other proposals have appeared in between and have given origin to various schools of biosemiotics, but the original difference about the nature of semiosis has remained.
In biology, the presence of semiosis at the molecular level is documented by the existence of the genetic code in all cells, and this implies that molecular (or organic) semiosis is produced by coding.
In the humanities, the dominant view is the Peircean concept that semiosis is always an interpretive process, and this implies that semiosis is produced by interpretation.
We have therefore two types of semiosis, one based on coding and one based on interpretation, and each of them represents phenomena that undoubtedly exist in Nature. There is ample evidence that animals are capable of interpreting the world, and this clearly means that Peircean (or interpretive) semiosis is a reality. But it is also evident that the rules of the genetic code do not depend on interpretation because they have been the same in all living creatures and in all environments ever since the origin of life.
The logical conclusion is that the two types of semiosis are both present in Nature and represent two distinct evolutionary developments. This, however, is precisely what the Peirce followers do not accept. If there is mind, interpretation and semiosis in animals, they claim, it is because there have been forms of mind, interpretation and semiosis in all previous living systems, including the first cells.
In reality, what we find in single cells is only coding and decoding, but the Peircean followers maintain that cells are still capable of interpretation because we can define decoding as a form of interpretation. Here we are then. One can say that all cells are interpretive systems simply by adopting an ad hoc definition of interpretation. Words, after all, are tools that we employ for our own purposes and we are used to give them multiple meanings, so where is the problem? The problem is not the use of words, that are indeed tools, but the result that we obtain with them, and in our case the result is two very different frameworks.
 Peircean biosemiotics is essentially a reformulation of known biological processes in Percean terms. It describes living systems with new words but does not discover anything new about them.
 Only a scientific approach to semiosis can lead to genuine discoveries, but this requires that we learn from experiments, not from ad hoc definitions, what are the semiotic properties of Nature.
In practice, biosemiotics has become increasingly identified with Peircean biosemiotics, a doctrine of life that is firmly based on Peirce’s philosophy. At the same time, however, the line of research that started with the discovery of the genetic code and advocated a scientific approach to the codes of life has not been abandoned, and it has become an independent field of research with the name of Code Biology.
From Biosemiotics to Code Biology
In 1962, Thomas Kuhn argued that “...a paradigm corresponds not to a subject matter but rather to a group of practitioners”, and a few years later a similar thesis was expressed by Mihaly Csikszentmihalyi, who stressed that a research field “includes all the individuals who act as gatekeepers to the domain. It is their job to decide whether a new idea or product should be included in the domain” (Csikszentmihalyi 1996).
According to these views, a discipline is what its gatekeepers say it is, and in that sense the identification of biosemiotics with Peircean biosemiotics was a perfectly legitimate operation because the board of the International Society for Biosemiotic Studies consisted almost exclusively of Peirce followers.
There was also another reason for that conclusion. Semiotics has become today a highly influential discipline and the Peirce industry has grown into an impressive enterprise that, like the Darwin industry in biology, is producing a steady flow of books, journals, congresses, grants and University positions. Like many other disciplines, on the other hand, semiotics is subdivided into ‘niches’, one of which is precisely its applications in biology. In Academia, as in Nature, all niches tend to be occupied, and this is why the relationship between semiosis and biology has become an increasingly active area in recent years. More than that. Many semioticians openly underlined “how exciting” it was for them the thought of “contributing to build a new paradigm for biology”, and this goes a long way to explain why virtually all semioticians were endorsing the Peircean approach in biosemiotics.
There was also another explanation. The scientists that were supporting the Peircean approach were often using the arguments employed by the supporters of Intelligent Design. In retrospect this is hardly surprising, because ‘interpretation’ is indeed a form of ‘intelligence’, and Peirce himself promoted the idea that there is an ‘extended mind’ in the Universe. The difference between the two cases is that in Intelligent Design the ‘interpreting agency’ is outside Nature whereas in Peircean biosemiotics is inside it. The common factor is that in both cases the results obtained by science are reinterpreted in a ‘postmodern’ framework simply by changing the meaning of a few key words.
By 2012, it became painfully clear to me that a scientific approach to the semiosis of Nature could not survive within the Peircean framework, and its future was seriously at risk. That is why, at the end of 2012, I resigned as editor-in-chief of Biosemiotics and together with eleven colleagues (Jan-Hendrik Hofmeyr, Peter Wills, Almo Farina, Stefan Artmann, Joachim De Beule, Peter Dittrich, Dennis Görlich, Stefan Kühn, Chris Ottolenghi, Liz Swan and Morten Tønnessen) founded the International Society of Code Biology (ISCB).
We also decided to leave no doubt about the scientific nature of that project, and to this end we explicitly wrote in the constitution of the new society that Code Biology is “the study of all codes of life with the standard methods of science”.
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 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 from him are still one of my most precious possessions. He wrote “A marvellous book…the presentation is simply beautiful…the theory is revolutionary”.
The discovery that there are many other organic codes in life in addition to the genetic code has not received much attention, so far, and therefore it has not modified the traditional view of biology. As a result, we still have a theoretical framework that contemplates only two codes in Nature: the genetic code that appeared at the origin of life and the codes of culture that arrived almost four billion years later. Which amounts to saying that there have been no other codes in between, and therefore that codes are extraordinary exceptions, not normal components of life. Such a situation can perhaps be illustrated with an example from the history of science.
In the 18th century, gravitation was the only known force in the universe and electricity was confined to the extravagant phenomena that were observed when some materials were rubbed together or when a kite was sent up in the sky during a storm to catch a lighting. It took a long time to change this view, but eventually it became clear that gravitation and electromagnetism are both universal forces and fundamental aspects of reality.
In biology we are today at the stage in which physics was at the times of Benjamin Franklin, when it became clear that electricity is everywhere in Nature and yet it was considered an extravagance. In a similar way, the dominant view today is that molecular copying is the sole fundamental mechanism of life and the genetic code an extraordinary singularity.
What is coming to light, instead, is that molecular copying and molecular coding (natural selection and natural conventions) are equally fundamental mechanisms. The world of molecular coding, in other words, is the other side of life that so far has remained hidden from sight just as electromagnetism was in the times of Newton and Franklin.
Code biology is the study of this new world, and it is, first and foremost, a new experimental field of research. From a practical point of view, it is important to underline that there are two distinct versions of Code Biology: a restricted version and a general one.
Code Biology in the strict sense is the study of all organic codes. Code Biology in the general sense is the study of all codes of life: organic codes, neural codes and language codes. This distinction is important because there are substantial differences between the two versions.
Code Biology in the strict sense is a fully scientific research field where the organic codes are studied with rigorous experimental methods and mathematical models. Code Biology in the general sense is, at the moment, a more speculative field because experiments on neural codes and language codes are much more difficult and in most cases we only have indirect evidence on them.
At the same time, we cannot concentrate exclusively on the organic codes. We must not lose sight of the larger picture formed by all codes of life and this is why Code Biology must study all of them, from the genetic code to the codes of culture, from the origin of life to the origin of language.
Code Biology, in conclusion, is a deeply interdisciplinary field that necessarily requires the contribution of many scholars: molecular and cell biologists, evolutionary and developmental biologists, neuroscientists, cognitive scientists, ethologists, ecologists, mathematicians, computer scientists, linguists and philosophers.
My whole scientific work has been dedicated to the search of the fundamentals of life and I am happy to say that I am finally seeing the dawn of the new biology.
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