Andrea Bracciali

Enrico Cataldo
email: enrico.cataldo@unipi.it

Luisa Damiano
email: luisa.damiano@unime.it

Claudio Felicioli

Roberto Marangoni
email: roberto.marangoni@unipi.it

Pasquale Stano
email: pasquale.stano@uniroma3.it

From Cells as Computation to Cells as Apps

Keywords: Synthetic biology, Programmable biology, Living hardware

de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

An emerging challenging view proposes to consider biology also as a quantitative and computational science. Distributed information processing and quantitative dynamics of massively distributed molecular systems are key factors when investigating life systems. Current breakthroughs in synthetic biology bring into play the possibility of programming such computational biological machineries. In this paper, we reflect on these recent ideas and the perspectives they open. As usually happens in interesting and developing fields, open challenges largely outnumber answers.

Modern genomics, proteomics, metabolomics and other -omics disciplines, have greatly improved our knowledge about the biochemical and functional network that regulates cellular life, according to a systemic approach. Despite these and other advancements, such as the gained insights into control structures (e.g., power-law in genetic control networks), [START_REF] Bhalla | Molecular computation in neurons: a modeling perspective[END_REF], and important links between network topology and functional aspects (e.g., Flux Balance Analysis studies [START_REF] De Lorenzo | Synthetic biology: discovering new worlds and new words[END_REF]) many functions are still to be understood. Quite recent progresses in biotechnology and synthetic biology make the computational paradigm move a step forward by bringing into play the programming aspect of computation. The theoretical possibility to control the cellular molecular machinery leads us to imagine programmable devices based on biological cells. This is one of the new frontiers of biology studies, where computer science, engineer, physics and affine disciplines work together to design new organisms or protocells able to perform targeted tasks in their biological environments. However, such a task-oriented or reductionistic view is questioned by the idea that biological systems, differently from classical computational systems, typically produce emergent behaviours. Schematically speaking, emergences are behaviours or properties that are observed at level of the living system as a whole, and result from the interactions, cooperative behaviours perhaps, of its components, and cannot be observed in the individual components as isolated, nor be deduced by their individual properties. For these reasons, beyond the scientific and technical challenges of addressing these issues, current trends have, on one hand, a significant impact on the philosophy of biology and computation, and on the other hand, might imply long-term changes in ethical and societal aspects. In the following we will discuss and survey some of what we believe to be the most interesting and promising current proposals and possible future scenarios.

Cells as Computation

Striking results in genomics have largely contributed to the view that cellular biology is a systems science: the complete knowledge of the DNA structure is not enough to describe its metabolic and regulatory functionalities, which depend on the whole cell state and its environment. Such systems are computational: "Many proteins in living cells appear to have as their primary function the transfer and processing of information. ... [they are organised] into biochemical 'circuits' that perform a variety of simple computational tasks, including amplification, integration and information storage. The imprint of the environment on the concentration and activity of many thousands of proteins in a living cell ... is like a 'random access memory' containing ever-changing information about the cell's surroundings." [START_REF] Bray | Protein molecules as computational elements in living cells[END_REF].

Also, the systems of interest can only be suitably described at a systemic level. It appears therefore quite natural to try to exploit the abstractions used to describe existing computational systems: "To understand biology at the system level, we must examine the structure and dynamics of cellular and organismal function, rather than the characteristics of isolated parts of a cell or organism. ... many breakthroughs in experimental devices, advanced software, and analytical methods are required. " [START_REF] Kitano | Systems biology: A brief overview[END_REF]. Also, from the Cells as computation paper: "We believe that computer science can provide the much-needed abstraction for biomolecular systems. ... the 'molecule-as-computation' abstraction, in which a system of interacting molecular entities is described and modelled by a system of interacting computational entities. Abstract computer languages ... enable simulation of the behaviour of biomolecular systems ... supporting qualitative and quantitative reasoning on these systems' properties." [START_REF] Regev | Cellular abstractions: Cells as computation[END_REF].

A large number of modelling languages and frameworks, often embedding reasoning capability on system behaviour, have been proposed. These include formal languages to describe molecular interaction as communicating computational distributed system and accounting for bio-features such as membranes and compartimentalised systems, e.g. [START_REF] Regev | BioAmbients: An abstraction for biological compartements[END_REF][START_REF] Cardelli | Brane calculi-interaction of bological membranes[END_REF]; stochastic aspects of molecular interaction, e.g. [START_REF] Priami | Application of a stochastic name-passing calculus to representation and simulation of molecular processes[END_REF][START_REF] Ciocchetta | Bio-PEPA: a Framework for the Modelling and Analysis of Biochemical Networks[END_REF]; rule-based systems, e.g. [START_REF] Fontana | The arrival of the fittest: Toward a theory of biological organization[END_REF][START_REF] Calzone | BIOCHAM: an environment for modeling biological systems and formalizing experimental knowledge[END_REF][START_REF] Danos | Rule-based modelling of cellular signalling[END_REF]; and Petri-Net based models, a formalism born in Bio-chemistry and widely used in computer science, see the survey [START_REF] Baldan | Petri nets for modelling metabolic pathways: a survey[END_REF]. See, e.g., [START_REF] Degano | Process calculi, systems biology and artificial chemistry[END_REF] and references therein for further details on such modelling frameworks, whose detailed description is here out of scope. The effort of providing refined modelling and verification frameworks is still ongoing, see. e.g., [START_REF] Parvu | Spatialtemporal modelling and analysis of bacterial colonies with phase variable genes[END_REF] on including the notion of space for reasoning on non-homogeneous spaces, so overcoming the so-far mainstream assumption of homogeneous reaction environments.

Further research directions have spawned from the approach, examples being the development of DNA-based technology for implementing the computational core of sensing and control processes of synthetic biological components [START_REF] Chen | Programmable chemical controllers made from dna[END_REF], and experiments on building RNA-based logical gates as the basis for the development of "in vivo logic processing" [START_REF] Seelig | Enzyme-free nucleic acid logic circuits[END_REF].

Towards Programmable Cells

While the modelling and formalisation of biological systems is still a challenge in mathematics, engineering, and bioinformatics, it is however evident that the development of novel practices in biology laboratories has the potential to support a transition from cell as computation to cell as apps, i.e., from computational to programmable biology. This is the reign of synthetic biology (SB). SB uses biological parts, devices and systems, e.g., molecules, molecular systems and networks, and (cellular) organisms, for engineering novel synthetic systems. Such systems behaves as applications that are running in their execution environment, for instance exploiting the underlying computational capability of molecules. The recent emergence of SB (mainly pioneered by US bioengineers) is based on the availability of powerful bio-analytical technique, especially highthroughput ones, the progress in synthetic capability (synthesis of genes), and the attitude of a young generation of scientists toward the blending and the convergence of biology and engineering.

One of the reasons why SB has become very popular in the last years is that it promises endless possibilities of manipulating organisms for achieving a predefined function [START_REF] Endy | Foundations for engineering biology[END_REF], although to date only microorganisms have been approached. Current and envisaged applications regard the production of biofuel, chemical intermediates for pharma-chem industry, destroying pollutants, drug development and delivery, diagnosis and therapeutic tasks, e.g. recognise and destroy cancer cells, and so on.

Synthetic Biology: Top-down and Bottom-up Approaches

Despite the term synthetic biology was coined by Leduc in 1912 [START_REF] Leduc | La Biologie Synthétique. Etudes de Biophysique, A. Poinat[END_REF], it is only thanks to recent trends in biological research, combining advancements in genetic manipulation, bioengineering and mathematical modelling, that a new flourishing interest grew around this frontier research field. As a consequence of this recent biotechnological progress, SB is currently seen as one of the most exciting and promising scientific arena, which has attracted scientists with different specialities, bioengineers, and also industrial parties. A possible definition of SB is the following: SB is the design and construction of new biological parts, devices, and systems; and the re-design of existing, natural biological systems for useful purposes (syntheticbiology.org). Useful purposes include (1) the production of any high-value compound from microorganisms (e.g., bio-fuel, drugs, high-value compounds for chemical industry, etc.); (2) the use of microorganisms for special non-medical applications (e.g., bioremediation, fermentation, hybrid living-organic or living-inorganic material, biosensoring); (3) applications in medicine (synthetic cells for attacking cancer cells, or infectious bacteria, virus).

Traditionally, SB operates according to a top-down approach: target functions to be implemented by biological tools (a part, a device, a whole cell) are firstly designed, and then the desired behaviour is obtained by a bioengineering approach, which assembles the tools within a suitable system. This view ultimately relies on the possibility of constructing biological tools just by designing and assembling "standard" biological parts (parts.igem.com) and bio-bricks, just like electronic engineering designs and builds tools starting from components [START_REF] De Lorenzo | Synthetic biology: discovering new worlds and new words[END_REF][START_REF] Endy | Foundations for engineering biology[END_REF]. Similarly to the electronic chassis, the cell with its core set of geneticmetabolic circuitry typically represents the biological chassis, where parts are implanted and operate according to a pre-defined program, at least in principle.

Although this view suffers of evident limitations (e.g., does not consider explicitly the role of emergent properties in complex systems, and in particular in living systems), it strikingly marks SB. Concepts such as standardisation, optimisation, modularity, orthogonalisation (eliminating between-parts interferences) have been introduced and implemented. All this is accompanied by mathematical modelling for the validation and correction of the new genetic-metabolic circuits. Besides being top-down from the viewpoint of design, mainstream SB is also top-down from the operational viewpoint, because it typically starts from living cells, and, via genetic manipulations, or by genome transplantation, transforms them to "synthetic" cells. A remarkable and successful example of such enterprise has been recently reported by Craig Venter's team, which succeeded in transplanting an artificial genome (designed a priori) into a biological receiver cell that obeyed to the new genome commands and proliferated accordingly [START_REF] Gibson | Creation of a bacterial cell controlled by a chemically synthesized genome[END_REF].

Following these recent and high-impact results the scientific community divided among SB-enthusiasts and those that were more cautious with respect to this new technology, which can potentially bring about the construction of dangerous disease-inducing novel organisms.

Clearly, the idea of constructing a synthetic cell that can be programmed to do something useful is very attractive, and it parallels the idea of applications, or apps, running on more traditional computational devices, such as computers and smartphones. Here, the cellular genetic-metabolic network is the chassis for installing a specific program (which is itself a genetic part which is recognised by the cell as a substrate for molecular operations, and at the end obtain a specific behaviour or pattern (e.g., producing a drug, or become fluorescent when a certain substance is present in the environment, etc.).

It must be recalled, however, that despite the straightforward analogies hardware ↔ cell and software ↔ genes (or functional components) are strong and widespread in SB, the peculiarity of "living computer" points exactly to the opposite concept of inseparability of biological parts, which evolved together, perform multiple interactions, and loose meaning when transplanted on a too different environment. Moreover, in contrast to electronic circuits, where wires guide electrons, every biological parts potentially interact with all the others in an unpredictable manner, hence undermining the possibility of modular design: adding a functional component to a system may break the component and also system functionality, or, alternatively, the functionality of a component is strongly dependent on their execution environment (a property that is clearly identified as undesirable and dangerous in software engineering). Finally, biological systems are characterized by emergent properties, which as explained above, mark a difference with traditional computers.

In addition to the described top-down perspectives, a new wave in SB embraces research focused on adopting SB practices as a novel approach for generating knowledge, the so-called understanding-by-building. This exciting possibility stems from the fact that SB offers, in principle, the possibility of constructing simplified cells (or even "minimal cells") that might still be functional, but obtained after a strong reduction of biological complexity, so that their behaviour, including emergent patterns, can be ultimately understood thanks to careful experimental observation and mathematical and computational modelling.

Although minimal cells could be obtained, possibly, following a top-down approach, it is the opposite route that is particularly interesting and a true novelty even within SB. This is the laboratory assembly of synthetic, or, more precisely, semi-synthetic [START_REF] Luisi | Approaches to semi-synthetic minimal cells: a review[END_REF], minimal cells (SSMCs), generally acknowledged as the bottom-up route. According to the understanding-by-building paradigm, the methodology that is currently under development aims at constructing minimal cells working as physical model to test some specific cellular functions, for example isolating a particular pathway or module from the intricate and indecipherable genetic-metabolic maze which characterises the whole cell.

Semi-synthetic Minimal Cells (SSMCs)

According to the so-called semi-synthetic approach [START_REF] Luisi | Approaches to semi-synthetic minimal cells: a review[END_REF] sets of biological macromolecules (DNA, ribosomes, enzymes) are encapsulated inside liposomes, i.e., bubbles made of a lipid membrane, generating SSMCs, which can be designed to produce proteins [START_REF] Calzone | BIOCHAM: an environment for modeling biological systems and formalizing experimental knowledge[END_REF], and then perform biological-like functions (Fig. 1). Thanks to the powerful self-assembly properties of lipids, and the resulting encapsulation of free solutes, cell-like systems emerge spontaneously, with mini- mal manipulation needs, although study aiming at optimising this process and preparing population of homogeneous SSMCs are ongoing. SSMCs can currently produce simple water-soluble functional proteins and some membrane proteins, which are often required for sensoring purposes, e.g. detecting molecules outside cells and trigger internal responses (see [START_REF] Stano | Compartmentalized reactions as a case of soft-matter biotechnology: synthesis of proteins and nucleic acids inside lipid vesicles[END_REF][START_REF] Ichihashi | Constructing partial models of cells[END_REF][START_REF] Blain | Progress Toward Synthetic Cells[END_REF] and references therein).

The design and construction of SSMCs by the modular assembly of genetic, regulatory or metabolic, circuitry in order to specifically exhibit some computation capabilities, presents some potential advantages (1) SSMCs are built from a minimal number of components, facilitating the modeling and the understanding of their dynamic behavior; (2) background and potentially interfering processes (always present in natural cells) can be eliminated in SSMCs; and (3) the synthetic cell behavior is predictable and programmable because the interaction among their components can be designed a priori [START_REF] Altamura | Giant vesicles as micro-sized enzymatic reactors: perspectives and recent experimental advancements[END_REF].

Very recent work also shows first steps toward multi-cellular systems. For example, it has been reported that lipid compartments can form clusters following simple adhesive forces [START_REF] Hadorn | DNA-mediated self-assembly of artificial vesicles[END_REF][START_REF] Carrara | Giant vesicles "colonies": a model for primitive cell communities[END_REF]. Protein synthesis is still possible in such assemblies [START_REF] Hadorn | Defined DNA-mediated assemblies of gene-expressing giant unilamellar vesicles[END_REF], and the idea of prototissue has been put forward, as supported by some pioneer work on membrane-to-membrane connective mojeties [START_REF] Ramundo-Orlando | Gap junction channels reconstituted in two closely apposed lipid bilayers[END_REF][START_REF] Moritani | Direct integration of cellfree-synthesized connexin-43 into liposomes and hemichannel formation[END_REF].

SSMCs originated from studies on the origin of life [START_REF] Oberholzer | Enzymatic RNA replication in self-reproducing vesicles: an approach to a minimal cell[END_REF], but actually can now be considered an à la carte design and construction of simplified, not necessarily living, cells for different applications. Autopoiesis, the key concept underlying all minimal cells, is a theory developed by Maturana Varela in the 70s [START_REF] Maturana | Autopoiesis and Cognition: The Realization of the Living[END_REF][START_REF] Luisi | Autopoiesis: a review and a reappraisal[END_REF]. It deals with the basic question"what is life?" and relies on two main hypotheses: [START_REF] Abel | Molecular mechanisms of memory acquisition, consolidation and retrieval[END_REF] The distinctive property of living systems is their autopoiesis, i.e., the capability of producing and maintaining their material identity (themselves) by producing their own components (metabolism); and (2) autopoiesis is a global property: it does not rely on physico-chemical components taken separately, but on the organisation of these components within living systems. In this sense, autopoiesis implies a strong link among synthetic cells and the concept of embodiment, connecting minimal life with minimal cognition, and emergent properties, as further discussed in Section 4.2.

According to the autopoietic theory, the required molecules for constructing a living minimal cell are only those needed for sustaining the self-production of all cellular components, membrane included. Recent genomic analysis of small microorganisms (endosymbiont living inside other cells) shows that about 200 genes suffice, constituting a minimal genome [START_REF] Gil | Determination of the core of a minimal bacterial gene set[END_REF]. For non-living systems, less genes are required, depending on the type of functions to be implemented.

Despite these advancements, the ultimate goal of constructing living synthetic cells is still far to be achieved.

Which computational power do SSMCs and other similarly engineered microorganisms have? They share with natural cells the capability of "chemical computing", i.e., processing information by manipulating chemical "signals". Chemical computing comprises molecular recognition, transformation, as well as some control activities, e.g., activation and inhibition of pathways, that largely resound constructs in traditional programming languages. The question about the relationship between biochemical computation and Turing completeness has attracted a lot of interest, e.g., [START_REF] Cardelli | Turing universality of the biochemical ground form. mathematical structures in computer[END_REF], and [START_REF] Winfree | Algorithmic self-assembly of DNA[END_REF][START_REF] Winfree | Universal computation via self-assembly of dna: Some theory and experiments[END_REF] on the Turing universality of DNA computing by reduction to grammars systems and specific classes of cellular automata. Several results prove universality of bio computation, others strive to define suitable theoretical model for what appears to be more suitably described as a reactive and distributed system, than a conventional Turing machine. Parallel cellular automata can be an example of such models. Moreover, probabilistic and stochastic phenomena play an essential part in bio computation, calling for models that account for that. Markov chain based models and the approach developed by Gillespie [START_REF] Gillespie | Exact stochastic simulation of coupled chemical reactions[END_REF] to describe biochemistry are noticeable examples.

Bio Apps: What Computation?

The several similarities between Turing computation and Bio computation should not lead to wrong conclusions. Not surprisingly, Apps and BioApps behave differently. We will discuss in the following three fundamental aspects, viz. emergent behaviour, embodiment and the possibility of a Turing test for communicating cells, which can help in such a comparison.

Emergent Behaviour

Among emergent behaviour, a notably example is given by morphogenesis. In an influential paper [START_REF] Turing | The chemical basis of morphogenesis[END_REF], Alan Turing suggested that a system of intercellular reaction-diffusion molecules, i.e., of interacting chemical substances diffusing through a tissue, could underlie morphogenesis. Starting from a homogeneous chemical system, some structures can emerge, activated by random inputs, due to the instability of the chemical complex itself. Six emerging spatiotemporal chemical structures could be generated and one of these could underlie differentiation. Turing' s thesis has been recently confirmed on experimental ground by [START_REF] Tompkinsa | Testing turing's theory of morphogenesis in chemical cells[END_REF], for homogeneous and heterogeneous systems. It is worth mentioning that morphogenesis is at the basis of regenerative medecine: "Regeneration recapitulates in part embryonic development and morphogenesis" from [START_REF]Foundation of Regenerative Medicine[END_REF]. Morphogenesis is an emergent phenomenon in the sense that it cannot be understood by considering the several part of the system in isolation but only as a result, not even predictable, of the interaction of all the components.

Embodiment

As it has been evidenced before, while the current methodology for synthetic cell construction is based on modern SB, and in particular to the convergence between liposome technology and cell-free systems, the theory of autopoiesis shapes, as a theoretical framework, the long-term goal of constructing a living synthetic unit in the laboratory.

Synthetic cells aim to be, therefore, molecular implementations of autopoietic (self-producing) systems whereby the internal (spatial and dynamic) organization not only accounts for the production of all components, as required from a purely biochemical balance (and maintenance of a topological unit in the space as well), but it is also a pre-requisite for displaying minimal cognitive features.

Autopoietic synthetic units, if and when they will be realised, will perform minimal cognitive dynamics. According to the autopoietic theory, here cognition is viewed as the capacity of an autopoietic system of entering in and maintaining a relationship of structural coupling with its environment, and thus facing and adapting to external changes by performing internal (metabolic) changes without loss of its autopoiesis. In other words, the system will be a cognitive system at a minimal complexity level, and this will be realized fully by the synthetic molecular implementation of the minimal autopoietic organization.

Synthetic cells, realised as minimal autopoietic synthetic units, might be the first fully embodied minimal cognitive systems produced in the laboratory, and for this reason very significant in the field of Embodied Artificial Intelligence (EAI). Synthetic autopoietic units could be able to respond to external input stimuli by sensory-motor coupling, by integrating and compensating the perturbations that can be accommodated in the autopoietic organisation. Interaction with the environment, and with other autopoietic (synthetic or natural biological) units, would might lead to the emergence of new behaviours, among which behavioural coupling and communicative interactions. The meaning of the latter would not be defined a priori, but generated from the autopoietic system.

The experimental attempts of constructing autopoietic synthetic units are then relevant for three main reasons: (1) to further understand the autopoietic and cognitive aspects of biological systems and, in particular, biological cells, providing a theoretically grounded and fully tuneable model based on molecular embodiment; [START_REF] Alberini | Mechanisms of memory stabilization: are consolidation and reconsolidation similar or distinct processes?[END_REF] to study AI in a more biologically-rooted way at a level of minimal complexity; (3) to move forward more complex systems such as hybrid bio-mechanical robots and, more in general, intelligent systems according to a radical embodiment perspective.

From a more general viewpoint, the development of synthetic cells realised as minimal autopoietic units points at enforcing a paradigm shift from the tradi-tional computationalist cognitive science (cognition as elaboration of exogenous information) to the embodied one (cognition as generation of internal meanings for external events), and therefore understanding first, and developing later, systems capable of adaptive responses to the wide bandwidth of physical communication channel by means of patterns of sensory modalities.

A Turing Test for Communicating Cells

The growing ability of synthetic biologists to realise synthetic cells capable of encode, send, receive and decode chemical signals, translates in both practical and conceptual advancements.

From the practical viewpoint, as remarked in Section 3.2, these advancements might lead to synthetic cells capable of communicating with natural cells and pave the way to future smart drug delivery systems. LeDuc et al. [START_REF] Leduc | Towards an in vivo biologically inspired nanofactory[END_REF] put forward a lucid vision of such an application, introducingthe concept of a "nanofactory" to be introduced in the body to convert pre-existing materials into therapeutic compounds, or transform molecules that a patient is unable to process, due to some medical condition, into other compounds that the body can process.

An interesting and somehow provocative conceptual scenario has been devised, on the other hand, by Cronin, Krasnogor, Davis and collaborators in 2006 [START_REF] Cronin | The imitation game-a computational chemical approach to recognizing life[END_REF], arguing that a sort of Turing test, based on minimal communication skills, could help to determine whether a system is alive (at the cellular level), bypassing the question of what life is, as the original Turing test was devised to determine whether a system is intelligent, bypassing the problem of defining what intelligence is. The authors describe how such kind of test could help in the field of artificial cellularity, and for the recognition of life in general. In this re-discovered cellular imitation game the setup is such that a synthetic cell must imitate a natural cell. The imitation becomes perfect when a natural cell as interrogator cannot distinguish a natural from a synthetic cell. Even if not explicitly said, the Turing test for synthetic cells would rely on chemical communication.

It is however evident that the Turing test suffers of some limitations. In particular, it allows only a superficial recognition of intelligence. As it has been often remarked, the artificial/synthetic imitation of, or resemblance with, the natural-biological partner could only be superficial and exterior, without implying the same generative mechanism. This caveat is particularly evident in attempts of comparing AIs with human intelligence, because it is conceivable a machine that imitates some aspects of human reasoning without sharing with human brain (or better, with the human body) the same experience in terms of autonomy, embodiment, emergence, sense-making. Does a Turing test based on synthetic cells suffer of the same or similar limitations? Due to the intrinsic embodied nature of autopoietic synthetic cells and of their minimal cognitive features, there is a significant difference with a computer simulating the human intelligence, and this difference is due to the intrinsic embodiment of synthetic cell processes. At this minimal level, will the synthetic/artificial cells really reproduce the cognitive pattern of a natural-biological partner? Will the synthetic vs. natural barrier indeed become ill-defined and possibly disappear? While it is still not possible to reply to the above questions, research is progressing from the experimental side. After the pioneer work of Davis [START_REF] Gardner | Sugar synthesis in a protocellular model leads to a cell signalling response in bacteria[END_REF], based on a chemical cell (a chell) sending a signal to the bacterium Vibrio harveyi, and the more recent SB approach by Mansy [START_REF] Lentini | Integrating artificial with natural cells to translate chemical messages that direct E. coli behaviour[END_REF], a research program is currently under development in our laboratory based on acyl-homoserine-lactones, which are simple quorum sensing signal molecules used by bacteria [START_REF] Stano | Semisynthetic minimal cells as a tool for biochemical ICT[END_REF].

Future Perspectives

In this section we will illustrate some possible directions for the creation of programable synthetic cells and applications in the field of neurochemical processes underlying memory, given their relevance in the human mental health, from traumatic stress disorder to memory disfunctions.

Towards Synthetic Cells 2.0

Although it is easy to imagine how synthetic cells can be constructed, their actual realization in the laboratory is still difficult. As it has been remarked in Section 3.2, the current artificial cell-like systems are quite limited in terms of functions implemented, and, importantly, they are not autonomous with respect to most of the important features, such as energy generation, self-reproduction, control of internal dynamics, and so on. In other words we are still far from constructing a truly autopoietic cell.

It is nevertheless possible to sketch some possible scenarios for the next generation of synthetic cells, maybe as a roadmap for synthetic cells 2.0, at least to recognize what seem, today, the future directions of this field.

First, the development of synthetic cells which could communicate with biological cells is one of the most intriguing aspects. Synthetic cells that are able to produce, manipulate, and respond to biochemical signals in a controllable and programmable way can be powerful tools for new bio-chemical ITCs [START_REF] Nakano | Molecular Communication Technology as a Biological ICT[END_REF][START_REF] Nakano | Molecular Communications[END_REF]. This fascinating path can be approached simply by extending current technology to molecular circuitry specifically designed for chemical signalling. Even if not alive, communicating synthetic cells could play a role in conceptual and applicative advancements.

Second, the ultimate goal of semi-synthetic minimal cell research is, of course, the creation of a synthetic cell capable of re-producing itself (i.e., all its parts, membrane included) by means of internal mechanisms and without intervention from outside. Such a cell would be autopoietic, but it is an open question whether it would be alive. In contrast with the early position of autopoiesis proponents, for whom an autopoietic system is alive, it has been recently argued that autopoiesis is a necessary yet not sufficient condition for being alive [START_REF] Bitbol | Autopoiesis with or without cognition: defining life at its edge[END_REF].

Third, another interesting research direction, which is currently pursued (Damiano and Stano, in preparation) is the connection between the SB approach and the field of artificial intelligence (AI). Can SB (i.e. synthetic cells) be useful for the "synthetic exploration" of natural cognition, and in particular minimal cognition? Embodied AI is generally concerned with the design and construction of robots, and especially the cybernetic control of movements, by means of sensori-motor coupling. However, working in the biochemical domain -which is the domanin where life actually originated -offers several advantages for developing embodied AI (a sort of bio-chemical AI). This implies a necessary reduction of complexity in AI goals, but on the other hand molecular embodiment can be the only way to approach the natural performances of biological systems. They indeed function by exploiting macromolecules, their interaction with environment and with other molecules, and their structural capability of modify themselves in response to some stimuli. All this means that starting from minimal synthetic cell it would become possible to construct and study minimal autopoietic cognitive systems so to generate a truly embodied AI.

Programming Brain Processes

The high throughput of data in neurobiology have stimulated the development of theoretical models of neural processes. There has been a lot of progress from the publication of the Hodgkin-Huxley model that elucidated the mechanisms of genesis and propagation of the action potential. Since then, models of interneuronal communication, dendritic spines and synaptic boutons dynamics, neuromodulation, plasticity and development have been proposed [START_REF]Modeling in the Neuroscience -from Biological Systems to Neuromimetic Robotics[END_REF][START_REF]Encyclopedia of Computational Neuroscience[END_REF].

Neuronal activity can be measured in the living brain and correlated with ongoing behaviour. To overcome correlation and investigate causal impact of neuronal activity to behaviour, new techniques have been developed, controlling single neurons in a living brain with high spatiotemporal resolution: optogenetics let us control neuronal activity in-vivo by using photons, and optogenetics actuators can be placed in specific cell types gaining high spatiotemporal resolution. To program animal behaviour by manipulating neuronal activity has been proved possible but improvements in models and techniques are needed [START_REF]Handbook of Neural Activity Measurement[END_REF].

Synaptic plasticity is understood to be one of the modality underlying learning and memory processes, whose mechanisms, at molecular and cellular level, have been at least in part elucidated during the last decades, as reviewed in [START_REF] Kandel | The Molecular and Systems Biology of Memory[END_REF]. Several insights have been obtained on the spatial and temporal distribution of memory, on how many tipes of memory exist and on the molecular and structural mechanisms of some forms of memory. Memories can be classified as explicit memory, also called declarative memory, regarding facts and events and implicit memory, also called nondeclarative memory, regarding perception and motor skills. Another feature of memory is its duration. One can distinguish short-term, intermediate-term and long-term memory.

Biological memory storage is the result of the interaction of several processes. Interestingly, long-term memory can be divided into four stages: learning, consolidation, storage and retrieval [START_REF] Wang | Molecular and systems mechanisms of memory consolidation and storage[END_REF]. During the retrieval, update and integration of a given memory with other memories, it is possible to obtain destabilization and restabilization of that memory. Depending on the temporal stage of a given consolidated memory, the retrieval can yield a destabilization of the memory traces and a possible change of them [START_REF] Alberini | Mechanisms of memory stabilization: are consolidation and reconsolidation similar or distinct processes?[END_REF][START_REF] Abel | Molecular mechanisms of memory acquisition, consolidation and retrieval[END_REF][START_REF] Mckenzie | Consolidation and reconsolidation: two lives of memories?[END_REF]. A complex molecular machinery is involved in such memory processes [START_REF] Ramakrishnan | Memory switches in chemical reaction space[END_REF]. Neurochemical computation regards not only neuromodulation, homeostasis, development and cellular housekeeping but also pattern detection and memory. It s believed that chemical computation is hundred times the electrical one [START_REF] Bhalla | Molecular computation in neurons: a modeling perspective[END_REF].

Informally speaking, such processes could be seen as a molecular foundation of psychology, which manipulates and heals disturbing memories through recalling them [START_REF] Dudai | Consolidation: fragility on the road to the engram[END_REF]. Can such molecular machine be programmed? Which are the implications?

Concluding Remarks

We have considered analogies between in-silico and in-vivo computation, according to a consolidated research approach which informs the field of systems biology. Furthermore, we have pushed further such an analogy, discussing the possibility of programming computational life systems, which is the goal of the currently strongly developing field of synthetic biology. We have presented current results and open issues of specific approaches in synthetic biology, mainly in the area of semi-synthetic minimal cells. Finally, we have considered both some of the differences between in-silico and in-vivo computation, and pointed out a few possible future developments, such as possible interactions of synthetic and natural cells, and the possibility of programming cells that play a role in brain processes.

This is an overview of an ongoing cross-disciplinary revolution that, we believe, will transform both computational and life sciences, with impacts on several aspects of our daily life, such as novel therapies, and production of bio-energy and food, among others.

Such relatively recent emergence of the computational and informational approach to biology has generated novel views and great research opportunities for both biology and computer science. It is beyond the scope of this work discussing the historical roots and perspectives of these achievements, which raise important questions in the epistemology of biology (we refer the interested reader to, e.g., [START_REF]Catalyzing Inquiry at the Interface of Computing and Biology[END_REF].) However, we would like to emphasize that it is crucial to support the development of this undoubtedly fruitful approach through a critical reflection on its possibilities and limits, and also through a related pluralistic epistemological attitude, oriented not to oppose it, but rather to complementarily integrate it with other existing approaches able to produce different scientific views on life.

Fig. 1 .

 1 Fig. 1. SSMCs. (a) Biochemical compounds, e.g., DNA, enzymes, ribosomes, tR-NAs, small molecules, are encapsulated within liposomes, i.e. hallow spherical microcompartments made by a lipid membrane. (b) Confocal images of "giant" liposomes whose lumen and membrane have been stained with fluorescent dyes (rendered in gray scale).

Acknowledgements. PS and LD thank Pier Luigi Luisi for insightful discussions on Maturana-Varela autopoiesis, cognition, minimal life, and embodiment.


Vladimir A Kitov
email: vladimir.kitov@mail.ru

Valery V Shilov
email: vshilov@hse.ru

Sergey A Silantiev
email: ssilantiev@hse.ru

Trente ans ou la Vie d'un scientifique

Keywords: Anatoly Kitov, automated management systems, unified state network of computer centers, EGSVTs, OGAS, ASU :3

Introduction

The life and works of outstanding Soviet scientist Anatoly Ivanovich Kitov (1920-2005) are attracting the attention of Russian and foreign historians of science and of writers and filmmakers as well. It is not surprising because his biography is full of great ideas and plans, pioneering works and dramatic episodes. These are the cruel battles in the World War II, the struggle for the recognition of cybernetics in the USSR, the very first monographs on computers and programming in this country, etc.

In just a few years after the appearance of the first brochure about Kitov [1] two books [12, 13] and dozens of articles have been published. Some of them concern his biography [2, 3, 8], others analyze his organizational activity [11], his struggle for the recognition of cybernetics [14], describe his scientific work in the programming and design of algorithmic languages [4, 9], etc. Indeed, Kitov opened a number of scientific paths in the field of computer science. He was the first in the USSR who wrote textbooks on electronic computers, programming, algorithmic languages and automated management systems (AMSs).

He developed the fundamentals of AMSs for defense purposes and applied great efforts for the introduction of computers in the military sphere, economy and medicine. His scientific works, monographs and articles, including those written in co-authorship with such prominent scientists as Axel Berg, Alexey Lyapunov and Sergey Sobolev during 1955-1962, have played an important role in the development of cybernetics and computer science in the Soviet Union.

In different periods of the scientist's life various of his works came to the forefront in different fields where computers could be used, such as warfare, economics, health care, program and information retrieval systems. However, the main idea of his entire scientific activity, originated in the late 1950s, was the vital necessity for USSR to create a nation-wide AMS. Besides technological breakthroughs, Kitov saw also advantages in the application of scientific methods to the management of the country and its economy, and in the transfer of a state power to a generation of comprehensively educated people, not blinkered by communist dogmas. He considered the implementation of this project as a kind of bloodless revolution in which along with the widespread introduction of the most modern computer technologies there would be a natural transfer of power from the state to the people who understood these technologies. He tried to explain the significance of his proposals to sequentially changing Kremlin leaders for three decades. The analysis of Kitov's attempts to establish a dialog with these leaders is the subject of the present paper.

First Proposals

At the beginning of 1960s the USSR economic complex consisted of hundreds of thousands of enterprises. The expansion of the economy was accompanied by an increase of complication of its management. The demand to achieve a planned balance of economy required the processing of huge amounts of data, and the coordination between all the sectors and spheres of industry. It was obvious that the flow of economic information had become too extensive to manage it manually or with the help of mechanical or electromechanical calculating devices. In the state management there was an urgent need to use computer technologies and automated management systems built on their basis [15].

Kitov was the first who raised the problem of the necessity of a unified management system for the national economy and military-industrial complex in the USSR based on computer technologies [5, 17]. Kitov stated for the first time his ideas concerning the restructuring of economy management of the Soviet Union by building a countrywide computerized management system based on a unified state network of computer centers in the 1958 brochure "Electronic computing machines" [START_REF] Dolgov | The Icebreaker. Some Pages from Biography of Anatoly Ivanovich Kitov (Ледокол. Страницы биографии Анатолия Ивановича Китов)[END_REF] .

At the end of the 1950s, while being the Deputy Chief of Science in Computing Center No. 1 of the Ministry of Defence, he developed the project of computers application for the management of Soviet economy, reducing the influence of subjective factors in decision-making and greatly increasing the efficiency of industrial and transport enterprises. Technically he considered AMSs as a network of thousands of computer centers covering the entire territory of the USSR.

In January 1959 Kitov sent to the First Secretary of the Communist party of the Soviet Union (CPSU) Central Committee and Chairman of the USSR Council of Ministers Nikita Khrushchev a letter in which he proposed to change radically the methods and means of the Soviet Union economy management by the "transition from manual and individual forms of management to automated systems based on the use of computers" [6].

This document is of great interest for historians [START_REF] Shilov | Anatoly Ivanovich Kitov's Biography: Stages of His Life and Scientific Work (Страницы жизни и научной деятельности Анатолия Ивановича Китова)[END_REF] . After the obligatory ritual addressing to the head of state, the author immediately moves to the essence of his proposals. Namely, to the fact that there was a "vitally important necessity" in the restructuring of the national economy and the creation of a nation-wide AMS. Those measures undertaken at that time, such as the "reorganization of management in industry according to a territorial principle", in the opinion of the author, although "have led to an improvement of the situation", did not eliminate the shortcomings in the work of the executive governmental bodies at all levels. In particular, he writes that systematic measures carried out to reduce administrative staff did not give the expected results, because they were implemented by using old methods and means of management. Kitov offered to put in the base of automated system application of scientific methods (methods of mathematics, rather than Marxist-Leninist philosophy and political economy: it is necessary "to move from general discussions about the advantages of socialism to solving the real problems raised by life") and computers. He concluded that the situation could be improved everywhere, all over the country, by using computers. In other words, Kitov suggested moving from the subjective and voluntaristic style of management to AMSs. He stressed that this would allow using in full such features of socialist system as the planning all over the country and the principle of centralized management. The introduction of AMSs will allow to make a real impact not only "on words", significantly reducing the extremely extended bureaucracy of the country.

Kitov proposed to build the AMS gradually: at the first stage electronic computers were to be installed in economic councils, ministries, departments, and the largest enterprises as well. Then the separate computers were supposed to be connected by the "automatic communication lines in more or less large complexes". Then these complexes (computing centers) should be integrated to the nation-wide AMS. Later on, Kitov named it EGSVTs [START_REF] Kitov | Anatoly Kitov -Pioneer of Russian Informatics[END_REF] .

An important thesis of his letter is that all efforts are doomed to failure because of the reaction of opposing forces whose interests would be imminently infringed by the wide automation of management processes. To avoid this, a "special, very authoritative" state body (no less than of a state ministry level) responsible for the introduction of AMSs in the country should be established. This body had to "be able to carry out control and analysis of the work of various administrations, central state boards, committees, individual institutions and enterprises, to develop projects for automation and reorganization of their activity, providing the mandatory implementation of the planned measures".

Leonid Brezhnev, at that time the Secretary and Member of the Presidium of the CPSU Central Committee, considered Kitov's letter to Khrushchev. He asked Kitov to clarify the essence of his proposals. Later on, in conversation with Professor Pavel Muzychkin, Kitov recalled this visit:

"They summoned me to the Central Committee. At that time these issues (science and technology, ndr) were supervised by Leonid Brezhnev. By then he was a rather progressive person. He told me: 'Here you are offering this and that. But we use a rather different approach. If there is any problem, we organize meetings with Soviet proletarians and kolkhozniks. We discuss with them. After that we make decisions'. And you know, Pavel Arsenovich (Muzychkin, ndr), I answered him plainly:

'Leonid Il'ich, if you get sick, would you also call for the workers and kolkhozniks to consult or listen specialists who know how to treat the disease?'" [12, p. 265-266].

Kitov's letter was written on the eve of XXI (extraordinary) Congress of the CPSU, held from January 27 to February 5, of the same 1959. We believe that the letter had a significant influence on science and technology policy of the USSR in the field of computer technologies, although the resolutions of this congress did not show directly this fact. Referring to Congress approved "control figures of the national economy development in 1959-1965" [START_REF] Ogandzhanyan | Anatoly Ivanovich Kitov's Contribution in Formation and Development of the Russian and World Informatics (Вклад Анатолия Ивановича Китова в становление и развитие отечественной и мировой информатики)[END_REF] , it is easy to see that they are mainly quantitative indicators, talking about the implementation of the "historic task -to catch up and overtake the most developed capitalist countries in the production sphere" [START_REF] Kitov | Anatoly Kitov: Technology vs. Ideology. The story about first project of nationwide computer network[END_REF] . It was not noted the emergence of a fundamentally new phenomenoncomputers. For example, computers are only mentioned in the section devoted to the successes of Soviet science and technology: a short list of the achievements in nuclear industry (the first in the world nuclear power electric station, nuclear-powered icebreaker "Lenin" and the world's most powerful particle accelerator), "serial production of intercontinental ballistic missiles", first artificial Earth satellite and at the very end of the document is noted that "a number of high-speed electronic machines have been designed" [START_REF] Kutejnikov | Automated Management System for the Soviet Union: A 1959 Letter from A[END_REF] . However, these machines were supposed to be used only for production purposes: "Wide prospects in the automation of production processes are opened by the achievements of computing technology. The application of modern computers for industrial processes allows selecting and maintaining automatically the most optimal technological process" [START_REF] Kutejnikov | The Last attempt to revive the Project of the National System of Automatic Control of the Economy (OGAS): A.I. Kitov's[END_REF] .

The possibility of the application of computers for other purposes was not even mentioned. Moreover, computers were not in the priority list of engineering products planned to be increased significantly (for the state of the Soviet computer industry in 1948-1960 we refer to [10, 19]).

However, as recalled by Vladimir Isaev, one of the Kitov's colleagues, after the Congress a special government commission chaired by the famous Soviet scientist and radio technician Admiral and Academician Axel Berg was organized according to a joint decree of the CPSU Central Committee and the USSR Council of Ministers for considering Kitov's letter. The Commission endorsed all the initiatives of the Deputy Head of the Computing Center No. 1 of the Ministry of Defence, colonel Kitov [START_REF] Meshcheryakov | The Interrupted Flight (Прерванный полёт)[END_REF] . In June 1959 an All-Union Conference was held, which proclaimed a policy of "accelerated development and application of computers and the widest possible introduction of automation and mechanization in the industrial production in the USSR" [12, p. 144].

In the late June of the same year the Plenum of the CPSU Central Committee considered the problems of accelerating the technological progress in the industry. The following Resolution was adopted:

"Taking into consideration the great potential of electronic technology in the field of automation of industrial processes the USSR State Planning Committee, the State Committee on automation and machine building of the USSR Council of Ministers along with participation of the State Committee on radio-electronics of the USSR Council of Ministers and in coordination with the Soviet Republics are charged with the development of a plan for the introduction of radio-electronic technologies in all the sectors of the national economy" [START_REF] Kitov | Anatoly Kitov and ALGEM algorithmic language[END_REF] .

We may assume that Kitov's letter became some kind of a catalyst for the adoption of such important decisions on the development and introduction of computers. However, it should be noted that Kitov's main proposal to establish a countrywide AMS for economy on the basis of a nation-wide network of computer centers was not supported by the leadership of the Soviet Union. It seems appropriate here to quote Professor Ivan Pogozhev:

"From all of the character traits of Anatoly Kitov I would like to distinguish in particular:

-The ability to see first the new progressive directions in science and give to it all his power immediately, despite the troubles that it could have brought to him personally <...> -His total lack of veneration and fear of higher authorities. He always told the truth, in which he was convinced, to the authorities just as definitely and frankly, as to any of his friends" [12, p. 309].

Exactly these traits noted by memoirist suggested Anatoly Kitov to take a second attempt to "reach out" to the country's top leadership. In the autumn of 1959 he sent a second letter to Nikita Khrushchev, which brought him the most serious negative consequences. The first part of the letter contained a strong criticism of a number of executives and in turn of the leadership of the Ministry of Defence for being slow in the development and introduction of computers in practical work. The main part of the letter contained a detailed description of Kitov's project "Measures to overcome the shortcomings in the development, production and introduction of computers in the Armed Forces and national economy". Today this project is known among the specialists as the "Red Book" project. It was the first project in the USSR, which proposed to combine all the computers in the country into a unified state network of computer centers. In peacetime this network must have fulfilled both national economic and defense tasks, and in the state of martial law or the threat of war it must have switched totally to defense. Kitov characterized this nationwide computer network as network of "dual-use" or "dual-purpose": for the national economy and Armed Forces [1, p. 8].

However, the bold and innovative proposals of the scientist were not understood in the USSR highest echelons of power. Moreover, when CPSU Central Committee sent the second Kitov's letter to Khrushchev and his "Red Book" project for consideration to the USSR Ministry of Defence, it strongly criticized it. Thus, the CPSU Central Committee in fact directly initiated reprisals against the author of the progressive project on optimization of the country economy and army management. As Kitov recalled:

"The report I presented before the commission, headed by Marshal Konstantin Rokossovsky, contained a serious criticism of the situation concerning the use of computers, especially in the Ministry of Defence. This caused a negative reaction among the two dozens of listeners -mainly generals. They strongly opposed it: 'The army will not fulfill economic tasks!' As a result, the commission rejected my proposals, called them irrational, because according to their opinion it was not allowed to mix military and civilian tasks. In fact, the people from the power structures did not agree with me because many of them would have lost their high state positions due the widespread introducing of computer technologies. I was expelled from the Communist Party and dismissed from the post of Deputy Head of the Computing Centre No. 1, which I occupied since 1954" [14].

During the discussion of Kitov's proposals at the beginning of 1960 the witness and participant of those events Konstantin Kurbakov recalls that "... very negative voices of Communist Party functionaries and government officials sounded on all meetings: 'And who are those who will decide for us?', 'And where is the leading role of the Communist Party?' etc. … I remember what an unpleasant discussion was at the meeting in the State Committee on Science and Technology. Immediately after Kitov's report officials put forward the accusation that Kitov "proposed a substitution of centralized Communist Party economic state institutions in the country by computer based system of independent 'local barons'" [12, p. 236].

After some time, Kitov was also dismissed from the Soviet Army.

Two Decades of Miscommunication

Nevertheless, in spite of the reprisals Kitov continued his scientific activity. He spoke at various meetings and conferences (Fig. 1), published papers, and defended the idea of establishing a nation-wide AMS for the country's economy.

As stated in [6], "the Director of the Institute of Cybernetics of the Ukraine Academy of Science Victor M. Glushkov (1923-1982) picked up the original idea of Anatoly Kitov and did not let it die". Publications and proposals of Kitov on automation and management of the country's economy through the creation of EGSVTs attracted Glushkov's attention to this subject. Under their influence Glushkov radically changed the direction of his research work from mathematics to cybernetics and computer science. It is almost unknown that Kitov was a close friend of Glushkov and seriously affected his scientific activity. Glushkov creatively reinterpreted and re-worked the ideas and proposals of the "Red Book". In 1962 with the assistance of the President of the USSR Academy of Science Mstislav Keldysh he drew attention of First Deputy Chairman of the USSR Council of Ministers Aleksey Kosygin to the ideas of AMS. In 1960-80s a large-scale campaign for introducing AMS at the level of separate enterprises, institutions and agencies was launched in the country (ASU10 ). It seized hundreds of thousands of Soviet citizens and continued till the beginning of "perestroika". Anatoly Kitov in 1960s was Glushkov's deputy on the work carried out in the field of AMSs for the branches of industry (OASU). In 1964, a group of scientists and specialists including Kitov and led by Glushkov proposed a draft of the EGSVTs project. It was not adopted because of many long-term approvals. Somewhere in 1970s, the title EGSVTs was changed to OGAS [START_REF] Kitov | The 60th Anniversary of Computing Center Number 1 of the USSR Ministry of Defense[END_REF] , but this did not help to accelerate the work… Soviet leadership supported OGAS only on words, not taking any serious actions [START_REF] Dolgov | Kitov Anatoly Ivanovich -Pioneer of cybernetics, informatics, and automation control systems (Китов Анатолий Ивановичпионер кибернетики, информатики и автоматизированных систем управления)[END_REF] . In the national press and in the resolutions of various scientific boards and commissions a lot of words were said about the great significance of OGAS, but as the saying is -"Things haven't moved an inch".

At the same time many science officials were employed by OGAS and regularly received various benefits in the form of high-level positions, apartments, cars, etc. while the proposals on OGAS were endlessly discussed and coordinated by different public authorities, especially by the USSR State Planning Committee and the USSR Central Statistic Department (both of them had the status of State Ministry). Rewriting paper versions of the OGAS draft was ended only in the early 1980s. But even then this document has not been signed by the project scientific supervisor Glushkov, and it was not approved by other eligible state authorities as well. Thus, the OGAS project remained only on paper, "drowned" in the cycle of long-term interagency coordination due to the failure of USSR leadership to take the concrete decisions. Only a small part of Kitov's and Glushkov's proposals were realized.

Despite the dramatic result of his first appeals to the leadership of the country, Anatoly Kitov did not cease the attempts to "reach out" to the first persons of the Party and State over the next twenty-five years. He was well aware of Soviet society features and clearly realized that in the USSR, with its highly centralized system of state management, only the decisions and actions of higher officials might lead to a systematic and widespread introduction of AMSs and economic-mathematical methods. Between the late 1960s and early 1980s, Kitov addressed several letters to the leader of the country Leonid Brezhnev and some governmental instances. These letters contained constructive suggestions for improving the situation and detailed analysis of the current disappointing state of matter in the country with respect to computers, software, peripherals, communication equipment, and automation in general. However, his proposals were either not understood or did not reach the high level leaders. These documents are still awaiting investigation by science historians.

Kitov was concerned that separate ASU were created in large numbers but without coordination, without a unified state-wide planning and a permanent strong control over their development and implementation, and with enormous expenses of state funds and resources. The process depended upon the degree of desire (or unwillingness!) of various local bosses. Therefore, it is not surprising that the total effect of their application was insignificant. Of course, such an approach did not give the desired results. This, in turn, led to dissatisfaction and disappointment both at the highest and middle management levels.

In the mid-1980s Kitov again tried to attract the attention of the new leadership to the OGAS project. Being at that time the Head of the Department of Computer Engineering in the Moscow Institute of National Economy named after Georgy Plekhanov, he wrote in October 1985 a letter to the General Secretary of the CPSU Central Committee Mikhail Gorbachev [7]. In this message he actually summed up his almost thirty years of efforts for the introduction of computer technologies and AMSs in the USSR. He expressed his concern about the fate of the project and pointed out that in the 1960-70s the development of separate AMSs went on spontaneously in various enterprises, industrial branches and departments. Those developments were scattered, with no effective coordination between the ministries. This letter focused on two key theses. First, as it was mentioned earlier in the letter to Khrushchev, it was the necessity to establish the All-Union government body (Kitov named it "Goskomupr" [START_REF] Tuchkov | Pioneer of digital continent (Первопроходец цифрового материка)[END_REF] ) responsible for the realization of the program and control of all ministries, departments and enterprises in the field of ASU development and introduction. The second one was the necessity to subordinate that body directly to the Politburo of CPSU Central Committee, because this project could have been realized only with the continuous support of the top political leadership. Colleagues and members of the family of the scientist remembered that Kitov was convinced that the establishing of "Goskomupr" would be a sign that the top management of the USSR "not in words but in deeds" supported OGAS project. Only the existence of this body would have allowed the fulfillment of the work according to the coordinated centralized plans. During the disputes with the closest colleagues, he said firmly: "Without establishing of All-Union Ministry for ASU that reports directly to the Politburo the introduction of OGAS is impossible" [START_REF] Neskoromny | The man who brought Cybernetics from the secret library (Человек, который вынес кибернетику из секретной библиотеки)[END_REF] .

Apparently, it was simply unrealistic to carry out in any other way such a significant large-scale state-wide project in the framework of the socialist system. This is confirmed by the memoirs of the Academician Boris Chertok (one of the Deputies of the Chief Designer of Soviet space systems Sergey Korolev): "The system of mobilizing the economy was preserved since the Second World War. All plans must have been fulfilled certainly. Failure would have been punished severely. By inertia this style of work continued into the period of "cold war"... The active participation of the government and the coordinated work of high-ranking officials, scientists and developers was needed... It was provided by the Military-Industrial Commission, which was established under the authority of the USSR Council of Ministers and, in fact, top Party leadership. This Commission helped to solve many scientific and technological problems aroused during the implementation of the largescale projects" [START_REF] Kutejnikov | At the beginning of a computer era: The prehistory of the Project of the Nationwide automated management system of economy in USSR OGAS (На заре компьютерной эры: предыстория разработки проекта Общегосударственной автоматизированной системы управления народным хозяйством СССР ОГАС)[END_REF] .

In fact, Kitov suggested to solve the problem of the development of the economy AMS in the USSR as it had been done in case of nuclear weapon and space projects. Kitov's proposals to build an AMS and replace the stagnant Soviet bureaucracy by forcible bureaucratic methods, at first glance, are contradictory. However, here we see his clear understanding of the mechanisms of the Soviet system. Indeed, the abovementioned nuclear weapon and space projects are rare examples of successful solutions of complex scientific and engineering problems in the Soviet Union. The whole experience of Kitov convinced him that only the military (Ministry of Defence, or KGB), or a civilian agency operating under military-like discipline, could realize such ambitious nationwide project. Of course, neither in 1960 nor later the Goskomupr was established by the communist leaders. Already after the second Kitov's letter to Khrushchev they were aware that introducing a AMS in the USSR economy controlled by Goskomupr was a deathly threat to the Party hierarchy. The establishing of Goskomupr actually would have meant the organization of a countrywide structure, replacing significantly Party organs at all levels of power. Taking into consideration the absence of a purely economic stimulus, which could have forced enterprises and agencies to introduce ASU, it seems that the whole idea of automation of economy management was doomed from the very beginning. [START_REF] Neskoromny | The man who brought Cybernetics from the secret library (Человек, который вынес кибернетику из секретной библиотеки)[END_REF] Kitov's letter to the General Secretary of the CPSU Central Committee Mikhail Gorbachev from October 9, 1985 is presented in B Appendix. The document is published according to the signed and dated author's copy storing at the Polytechnic Museum of the Russian Federation (f. 228, d. КП 31862/1-2). We do not publish the Appendices to this letter. [START_REF] Kutejnikov | At the beginning of a computer era: The prehistory of the Project of the Nationwide automated management system of economy in USSR OGAS (На заре компьютерной эры: предыстория разработки проекта Общегосударственной автоматизированной системы управления народным хозяйством СССР ОГАС)[END_REF] Chertok, B.E.: Korolev entered the history of mankind. Russian space (Российский космос),

1, 12-15 (2007).

There is a handwritten note made by Kitov in November 11, 1985 (Fig. 2). It says that the instructor of Economic Department of the CPSU Central Committee Yury Samokhin called Kitov and informed him that his letter had been considered. Samokhin was authorized to answer the following: "Firstly, thank you for the help in such an important matter. Secondly, not all points of the letter are approved by the Economic Department. The Politburo of the CPSU Central Committee has many other tasks, beside the automation of the national economy management. There is a program on computing engineering adopted by Politburo in January 1985 and this is now the main document. The establishment of the State Committee on Computer Engineering is delayed". Anatoly Kitov asked to answer him in writing, not by telephone. But his request was rejected. OGAS project finally sank into oblivion during "perestroika". From 1987 to 1989 some laws were adopted, which provided the extension of enterprises autonomy. The main condition for the successful realization of the OGAS project -a rigidly centralized system of economy management -disappeared. On the other hand, OGAS project was already outdated by that time. The emergence and mass distribution in the West of personal computers required a revision of the basic principles of automated systems organization. This meant additional investments, which the Soviet government could not afford due to the growth of serious economic problems. The crisis of the late 1980s significantly reduced the financial capabilities of the Soviet government to fulfill an expensive project of management automation. All these factors buried one of the most ambitious and promising scientific and technological projects of the Soviet era.

However, the elderly scientist did not pile weapons and stop his attempts to express his views on the problem of economy management [16]. In 1987 he sent a long paper to the leading Soviet ideological journal "Communist", but it was rejected. The editor of the science and education section A. Antipov informed Kitov that they "do not consider it appropriate to publish" his article, because the editorial portfolio had already contained "a serial of materials relating to the problems of society informatization". Three years later, Kitov proposed to the same journal another article. The consultant of journal economic section N. Golovnin answered to Anatoly Kitov that his "material" under the title "The problem of the cardinal improvement of the national economy management in the political economy of socialism" was considered and rejected. Golovnin recommended to send the article to the special economic editions because in "Communist" "a limited attention is given to economic problems" (Fig. 3). This argument today produces a very strong impression, because the collapse of the socialist economy was the catalyst for the death of the whole Soviet political system... Unable to present his ideas in influential ideological venues, Kitov tried to explain them to the public. The last known Kitov's attempt to openly express his views was undertaken at the scientific conference in Penza in October 1989. He was a Chairman of this conference and many well-known Soviet scientists took part in it. The conference lasted two days and adopted a Resolution (it is presented in excerpts in Appendix C). The document strongly criticized the state of Soviet economy and predicted its imminent crash if appropriate measures would not have been undertaken. Among others measures, the introduction of mathematical methods and information systems were suggested. The Resolution contained many other interesting points. For example, it was outlined very clearly and firmly the ineffectiveness of some hastily established governmental (the State Committee on Computer Engineering and Informatics) and (pseudo-)public institutions (the Institute for System Researches and other institutions of the Academy of Sciences), parasitizing on the fashionable computer topic. In this document we see the recognition of the principle of centralized management and planning on a national scale as a fundamental one, but many sound ideas were also expressed. For example, the need of cooperating with the Western countries in the production of computers.

Of course, in the situation of economic collapse and growing political crisis of the Soviet Union this modest document had no practical consequences. Nevertheless, it remains a valuable evidence that not all the scientific community was in captivity of communist ideological demagoguery. Many specialists saw the real state of economy and science, and they tried to deliver their opinions to the governing authorities by all available means. Ignoring of the views of qualified professionals and the blind faith in the magical power of political spells contributed in a large extent to "the failure of senseless plans and worsening of crisis in the country", as was stated in the conference Resolution.

Apparently, Kitov's report "The role of modern computers in improving the management of enterprises and promoting the human factor" presented at the conference was the last speech on the main topic of his scientific activity.

Conclusion

Unfortunately, Kitov's thirty years attempts to establish a dialogue with the Soviet authorities failed. But the dialogue did not take place -it was only a monologue. Undoubtedly, it was caused by some features inherent to Soviet political system, which determined the relations between state and science (see for example [18, 19]).

In the opinion of Professor Gennady Meshcheryakov, "[…] one of the main reasons of the crisis of the USSR was the fact that the whole system […] suppressed outstanding innovators such as Anatoly Kitov, who was sincerely concerned about the welfare of his country" [8].

A Appendix

DEAR NIKITA SERGEEVICH! Heartily approving your reforms, I would like to report you, in connection with the 21 Congress of the CPSU, the following considerations related to the prospects of the development of our country.

At the present time, there is a vital need for a computerized system of administrative and economic management of the country through the application of scientific methods of management organization and electronic computers. <…>

The reorganization of the management in industry and civil engineering by a territorial principle has, of course, led to an improvment of the situation. But there are still serious shortcomings in the current and long-term planning, accounting, logistics, coordination of activity of separate enterprises and branches of industry as a whole, personnel training and distribution, effective use of finance, introduction of new technologies and so on. Ongoing systematic measures to reduce the administrative staff do not give the expected results, because they are realized by old means and leadership methods. These reductions are fictitious in their significance, because either vacancies are reduced or the fired staff immediately gets a similar job in other places. In addition, the financial sums saved on administrative personnel reductions are very small in comparison with the huge sums that our country loses annually due to shortcomings in the administrative management. The lack of accurate accounting, planning and control contributes to bureaucratism, irresponsibility and misuses.

The modern level of the development of the productive forces and the complexity and interdependence of the various branches of the national economy requires a radical change and improvement in the management methods by the transition from manual and personal forms of management to automated systems based on the use of computers.

It is very important to give the appropriate attention to this problem in the Report to the 21 Congress of CPSU. Besides the further increasing of industrial production, one of the main tasks of the future seven-year plan must be the automation of administrative and economic management with the help of computers. On this way the most important advantages of the socialist systemplanned economy and centralization of managementcould be used in full. The creation of an automated management system in our country will be a revolutionary leap in its development and will provide the complete victory of socialism over capitalism.

Automation of management processes will require a large scientific, technical and organizational work in two main directions:

1. The development of scientific methods and forms of management organization at various levels. Economists involved in this work must move from general discussions about the advantages of socialism to the solving of real life problems; 2. The evelopment and introduction of computers and other technical means of automation. Naturally, the development of an automated national management system should be carried out gradually in several stages. The first step should be the introduction of electronic machines in some of the largest enterprises, departments, committees, and ministries.

Later, these separate machines will be linked together by automatic communication lines in more or less large complexes and in future thet may be combined into a unified automated management system.

Already at the very first stage the introduction of machines should lead to a significant increase in management efficiency and a very significant reduction of administrative staff. However, it is clear that the reduction or elimination of any of management agencies can be made only after a complete introduction of the relevant electronic system in the reliable service.

Taking into account the political and economic importance of management automation in the country, the significant workload and that the introduction of computer machinery and, associated with this fact, staff reduction will be met with some resistance, it is needed to establish a special and very authorive body to carry out the work on a national scale. If we let things go without control and provide interested institutions the possibility to decide whether or not to automate their work, then our efforts will be doomed to failure. This body must control and analyze various administrative bodies, committees, individual institutions, and enterprises, must develop projects for the automation and reorganization of their work and must ensure the mandatory implementation of the planned measures.

The existence of such a special state body responsible for the correct scientific organization and automation of management processes will bring uniformity in the structure and activity of various departments and agencies, will allow widespread utilization of scientific and technological achievements and will give an immediate real economic effect.

The task of this body should include the organization of a relevant computer center network in the country and the control of its work. This is the most necessary because the large scale production of machines has been already planned, but preparations for their application still have not been provided. [

B Appendix

DEAR MIKHAIL SERGEEVICH!

Let me present you my thoughts on the analysis of the introduction of computers in the economy of our country for the last 30 years.

The purpose of presenting these materials is: a. To show that this is already the third time that an attempt to solve the problem of automation of the Soviet economy management on the basis of computers is presented, with about the same goals and objectives. The approach still remains the same, and, as before, there will be no progress if we do not change our attitude to this problem. b. To show that the basic methods and principles of automation of the national economy management, put forward 20-30 years ago, still keep their importance today. c. To present, at least partially, a description of the last stages of activity in the implementation of computers and automated management systems in our country and thus contribute to a more critical attitude to the plans and declarations that are put forward nowadays. It is obvious that the materials presented do not include all the works and publications about this problem for a given period. Only my own works are presented because they describe, in my opinion, the general character of the work and efforts in this direction [

C Appendix

RESOLUTION of the scientific conference on the theme "Role of the human factor and modern computers in the improvement of enterprise management", held jointly by the Moscow Institute of National Economy named after G.V. Plekhanov and the Volga Region House of Scientific and Technical Propaganda (Penza, 30-31 October 1989) 1. In the contemporary situation of the pre-crisis state of the economy one of the main ways to improve the management of enterprises, branches and the national economy as a whole according to perestroika aims is a wide application of automated accounting, planning and management systems based on modern computers. However, today an appropriate attention is not given to this very important problem <…> 2. Now there is an extremely difficult situation in the field of computer engineering and informatics in our country with the organization of mass production of modern computers, their application and introducing of mass standard ASU as well.

Computer industry, on which for many years has been invested heavily […], is unable to achieve the modern level of production. It is time to bring foreign companies in the business and establish joint ventures for the production of computers […], purchases of computers and software abroad should be expanded as well. […]

3.

[…] It is necessary to tighten control over the real use of the purchased computers and software and provide concrete economic effects of their application. 8. The basic principle of production (purchase) of computers in our country should be their application according to the unified state plan in specific management automated and information processing systems with a predetermined economic effect and period of realization

Fig. 1 .

 1 Fig. 1. Anatoly Kitov (scientific conference at Tashkent, 1963). Reproduced by permission from Kitov family papers

Fig. 2 .

 2 Fig. 2. Kitov's handwritten note, dated November 11, 1985. Reproduced by permission from Kitov family papers

Fig. 3 .

 3 Fig. 3. Letters from "Communist" journal. Reproduced by permission from Kitov family papers

4 .

 4 The country has established a great number of organizations, parasitizing on computer science and computer engineering. First of all, this should be noted for the State Committee for Computer Science and Informatics, […] the Institute for System Researches, Department of Informatics and Computer Engineering of USSR Academy of Sciences and various other institutions. It would be useful for the national economy and for the cause itself to liquidate them in the shortest time. Instead, an association of scientific and industrial enterprises should be established for the production and introduction of computers in the national economy. 5. Various automated management sub-systems are developed and introduced in the enterprises and their development is still continuing. It is necessary to analyze the existing projects, choose the best and make them standard for each branch of the industry. This would save a lot of money and resources. […] 6. It is necessary as soon as possible to organize the work on the development of unified schemes of management automation and information processing in the various types of enterprises […] 7. The State Research and Production Association of Computer Engineering and Informatics (it seems that A. Kitov means here the above mentioned State Committee for Computer Science and Informatics, ndr) must organize the State network of information computer centers […] carrying out a survey of enterprises, support and maintenance of typical automated systems of information processing and management.

  […] Chairman of the Conference Doctor of technical sciences Professor А. I. Kitov Head of the Computing Technology and Programming Department of the Moscow Institute of National Economy named after G.V. Plekhanov

Kitov, A.I.: Electronic computing machines (Электронные вычислительные машины). Znanie, Moscow (1958).

Kitov's letter to the First Secretary of the CPSU Central Committee and Chairman of the USSR Council of Ministers Nikita Khrushchev from January 7, 1959 is published in A Appendix. The document is published according to the signed and dated author's copy handed by his family to the Polytechnical Museum of the Russian Federation (f. 228, d. КП27189/20).

EGSVTs (ЕГСВЦ) -Russian abbreviation for "Edinaya Gosudarstvennaya Set' Vychislitel'nykh Tsentrov" (Unified State Network of Computer Centers).

XXI Congress launched the first (and the last) "seven-year country development plan" in the history of the USSR.

Extraordinary XXI Congress of the Communist Party of the Soviet Union. Verbatim report, vol. 2, p. 456. Politizdat, Moscow (1959).

Ibid., p. 468.

Ibid., p. 487.

The Minutes of Commission Proceedings have not been yet investigated by specialists, yet they could also be a very valuable historical source.

Plenum of the CPSU Central Committee. June 24-29, 1959. Verbatim report, p. 508. Politizdat, Moscow (1959).

ASU (АСУ) -is Russian abbreviation for "Avtomatizirovannaya Sistema Upravleniya" (AMS).

OGAS (ОГАС) -is Russian abbreviation for "Statewide Automated Management System for Collection and Processing of Information for the Accounting, Planning, and Management of the National Economy".

About the background and history of the project see for example[START_REF] Kutejnikov | At the beginning of a computer era: The prehistory of the Project of the Nationwide automated management system of economy in USSR OGAS (На заре компьютерной эры: предыстория разработки проекта Общегосударственной автоматизированной системы управления народным хозяйством СССР ОГАС)[END_REF].

Gosudarstvennyi komitet po upravleniyu (State Committee for Management).