Bernadette Bensaude-Vincent
email: bensaude@u-paris10.fr

Running Head: Self-Assembly Self-Assembly, Self-Organization: Nanotechnology and Vitalism 1

Keywords: biomimetics, hybridization, bionanotechnology, nature and artifact, chemistry, biology, cybernetics

Over the past decades, self-assembly has attracted a lot of research attention and transformed the relations between chemistry, materials science and biology. The paper explores the impact of the current interest in self-assembly techniques on the traditional debate over the nature of life. The first section describes three different research programs of self-assembly in nanotechnology in order to characterize their metaphysical implications: -1-Hybridization ( using the building blocks of living systems for making devices and machines) ; -2-Biomimetics (making artifacts mimicking nature); -3-Integration (a composite of the two previous strategies). The second section focused on the elusive boundary between selfassembly and self-organization tries to map out the various positions adopted by the promoters of self-assembly on the issue of vitalism?

Self-Assembly, Self-Organization: Nanotechnology and Vitalism

Put the different parts of a car in a big box, and shake the whole, will you get a car? This image is often used to express what self-assembly can achieve. 1 Spontaneous arrangements of small building blocks in ordered patterns or structures are ubiquitous in living systems, and they are crucial for designing at the nanoscale, where human hands and tools are helpless. Self-assembly is extremely advantageous from a technological point of view because it is a spontaneous and reversible process with little or no waste and a wide domain of applications ranging from nucleation of inorganic particles, formation of vesicles, monolayers, supramolecules, etc. Over the past decades, self-assembly has attracted a lot of research attention and transformed the relations between chemistry, materials science and biology. A bibliometric survey of the occurrences of the term "self-assembly" in comprehensive data-bases (the ISI: Science Citation Index/SCI and Social Science Citation Index/SSCI) by Sabine Maasden and Mario Kaiser reveals a spectacular increase over the past twenty years. 2 According to their survey about 10% of the papers devoted to nanotechnology address the concept of self-assembly. Among them a small portion (about 3%) are dealing with self-organization (176 over an amount of 5741 papers in the year 2005). A wide spectrum of self-assembly techniques have been developed and described in the technical literature. 3 The car metaphor is rather used in semi-popular publications. It is meant to emphasize the novelty of nanotechnology and the radical break with conventional top down fabrication techniques. On the other hand, it conveys a kind of magic power to nanoscientists. 4 The access to the nanoscale also triggers the ambition to create artificial cells and to unveil the mystery of the origin of life.

From a historical perspective, self-assembly strikes as a new episode in a long tradition of Faustian ambitions to rival with life. Paracelsus already claimed that alchemists could create an artificial human being, a homonculus in a test-tube. 5 Later on nineteenth-century chemists spread the legend that the synthesis of urea by Friedrich Wöhler destroyed the metaphysical belief in the existence of a vital force since chemistry was able to synthesize substances so far made only by living organisms. 6 It was not difficult however for physiologists such as Claude Bernard to ridicule their claims by pointing to the huge difference between their laboratory processes and nature"s processes. Chemists could certainly synthesize the products of life but could not imitate the ways of nature in their vessels and furnaces. 7 Thus their antimetaphysical claim proceeded from two confusions: between "organic" and "organized" and between product and process. However today chemists seem to be in a better position to silence Bernard"s objection. Self-assembly seems to open a path for emulating nature"s processes. Are we going to witness a new episode of the endless fight between vitalism and reductionism? Will history repeat itself? And to plagiarize Marx"s famous remark, while putting it upside down: shall we say that the first time it was a comedy and that the second time it could be a tragedy?

Three distinctive research programs

The purpose of this section is not to survey the various strategies of self-assembly at the interface between nanotechnology and biology, which are described in today"s scientific literature. 8 Rather I try to distinguish various research programs using self-assembly, to make a kind of typology. I do not claim that this tentative categorization does justice to the entire field. As I take for granted the antipositivistic claim that there is no science without implicit metaphysics, I will try to identify the metaphysical assumptions underlying the three categories here distinguished.

-1 -Using the building blocks of living systems for making devices and machines is the strategy that can be named hybridization.

-2-Biomimetics is making artifacts mimicking nature -3-Integration is a kind of composite of the two previous strategies. However like most composite materials this one is more than the sum of its ingredients as it rests on quite different metaphysical views.

The three research programs here described rely on the assumption that artifacts and natural systems share some features and often use the machine metaphor to describe living systems. But the metaphor works in two different ways. Either technological vocabulary is applied to living organisms and describes them as machines or organic metaphors are used to describe our devices and machines. In the 1970s, the French philosopher Georges Canguilhem noticed that the analogy between organism and machines always works one way: organisms being described in technological terms. 9 But nowadays it is more and more usual to describe machines in biological terms. The distance between machines and organisms tends to be blurred.

Hybridization

An obvious way to self-assemble the parts of our machines is to take advantage of the exquisite structures and devices selected by biological evolution. For instance, using biology to build nanoelectronic circuits that assemble without human manipulation. When Erez Braun, a biophysicist from Technion at Haïfa announced that he used the complementarity of DNA strands for making nanotransistors, the news was widely reported.10 Now it is current routine practice in the laboratory waiting for applications at industrial scale.

The designer of such machines borrow a specific material or device "invented" by biological evolution regardless of its specific environment. Indeed traditional technologies have been doing that for centuries. They used to extract resources such as wood, bone, or skin and process them to make a variety of artifacts. Similarly nanotechnology extracts a number of small units as close as possible to the building blocks of living systems (DNA, bacteria,..) in order to build artifacts from bottom-up. This strategy requires that the living cell be viewed as a collection of machines operating together. "Molecular machine" is a fashionable expression. It is currently used both by molecular biologists who describe DNA, RNA, enzymes, proteins as nanomachines and by materials chemists who are building molecular motors or rotors. Living systems are viewed as molecular manufactures and the analogy is often used as a proof that we can make it. But there is little chance that we can emulate nature, which spent billions of years for designing and perfecting high-performance structures capable of sustaining life. It seems more reasonable to start from the building blocks provided by nature -whether they be proteins, bacteria, micelles or colloids -in order to achieve our own goals. Steven Boxer, a chemist from Stanford who uses proteins as transistors in electronic circuits, thus describes his strategy: "We"ve decided that since we can"t beat them (biomolecular systems), we should join them".11 "Joining" may not be the most appropriate term for two reasons: i) biomolecular systems have to be decomposed in a number of elementary units, redefined as functionalities, and abstracted from their own environment; ii) they have to be processed and modified through genetic engineering to perform specific tasks in an artificial environment. To consider such uses as a form of partnership ("join") you have to consider that biological systems are fully and adequately described in terms of a collection of independent devices that can be abstracted from their environment and re-used in other environments.

In my view this strategy is more adequately depicted as appropriation of biological items in the dual sense of the term (at least in French): i) they are processed through various techniques (recombination, gene modification, …) in order to be adjusted and adapted to human purposes; ii) they become our intellectual property and can consequently be patented.

Further analysis of the model of machines underlying this strategy points to a number of characteristic features. In fact, the analogy between nature and artifacts is self-reinforcing. The more machines try to resemble living organisms, the more nature is artificialized. However, as shown from the chart below, molecular biologists do not care for shaping a consistent metaphor. Rather they pick up images from a variety of technologiesmechanical engineering, electrical circuitry, information technology…. A living cell looks more like a warehouse or a garage, than like a modern manufacture. More importantly the cell seems to be a collection of independent parts, each of them designed for performing a specific task. In this respect the cell machinery is a very classical machine, such as clocks. In classical or "Cartesian" machines, each individual component is assigned a definite function. 12 Each functional part is independent from the others and has to be assembled together by a specific tool. For instance, Drexler"s universal assemblers, modelled on ribosomes, pick and place atoms to assemble them. In this model of machine where each task is correlated with one component, self-assembly becomes a self-contradictory notion. For the machine to be ideal, assembly has to be a functionality belonging to an individual unit rather than a property of the whole. All spontaneous tendency to self-assemble, to stick together is an obstacle.

Biomimetics

An alternative strategy is to mimic nature. Even before the nano-tsunami, self-assembly has prompted collaborations between materials scientists and biologists. 13 Materials scientists who turned their attention to natural composites such as wood, bone, muscles, or natural fibers such as spider silk were fascinated by nature"s multifunctional structures and efficient processes. For Mekmet Sarikaya et Olhan Aksai " biomimetics is the study of biological structures, their function, and their synthetic pathways, in order to stimulate and develop these ideas into synthetic systems similar to those found in biological systems. " 14 The phrase "synthetic systems" suggests that the machine metaphor no longer guides the interpretation of self-assembly and that a more systemic approach prevails.

In fact, biomimicry cannot be just copying a model. Mimicking biology never meant duplicating the original in all its details or faking it, as could be the case with fine arts copies. Even when materials scientists mimic marine shells for making strong composites, or lotus leaves for making non-wetting glass, they do not make indistinguishable copies. They usually select essential aspects of biomaterials. Yet generally their model is less a living system than a local pattern or device whose performances are interesting for engineers.

When it comes to mimicking processes such as self-assembly, then the laboratory cannot exactly copy the model. Chemists usually operate at high temperatures, in high vacuum and with organic solvents, while nature is able to operate at room temperature, in rather messy and aqueous environments as well as in very extreme conditions. Nature provides inspiration rather than models.

Whereas designers trying to replicate a model have to acquire an in depth knowledge of its fine-grained structure and to look at details through the eyes of botanists, by contrast for 12 Bensaude-Vincent, Guchet ( 2007) 13 Sarikaya & Aksay (1995), Bensaude-Vincent, Arribart & al. (2002) 14 Sarikaya et Aksay eds, (1995) p.xi drawing lessons from nature, materials scientists have to abstract the basic principles and the major constraints at work in living organisms before designing their own behavior and strategy. The promises of self-assembly for nanotechnology have thus prompted a number of research programs in molecular biology and biophysics aimed at understanding the process of self-assembly such as protein-folding or the use of templates generating geometrical constraints.

As a result it is clearly established that self-assembly requires at least two conditions: i) reversibility is crucial for allowing the recombination of parts. Self-assembly relies on noncovalent bonds such as hydrogen -bonding, electrostatic or ionic bonds and labile interactions. ii) the information must be contained in the reagents, encoded in the components rather than provided by an external program.

Ironically the study of the basic principles of self-assembly led to conclusions emphasizing the distance between organisms and machines. This is a major result of nanobiotechnology that goes usually unnoticed. In biomimetic strategies, the convergence between nano and bio does not rest on similarities. Rather it requires the clear recognition of the differences between biological environment and technological environment. A number of contrasts are listed in the tentative chart below which should be refined and probably extended. Emphasizing the contrasts between conventional engineering and biological processes was typically Richard Jones"s enterprise in Soft machines. 15 Jones insists that biological machines work with Brownian motion and that "a different feature of the physics that leads to problems for one type of design may be turned to advantage in a design that is properly optimised for this different world". 16 The properties characteristic of the nanoscale, which are problems for conventional machines, will have to be used as positive opportunities by nanoengineers. Jones thus contrasted two "design philosophies" to make nanoscale artifacts. Conventional design is based "on the principles that have served us so well on the macroscopic scale would rely on rigid materials, components that are fabricated to precise tolerances, and the mutually free motion of parts with respect to each other. As we attempt to make smaller and smaller mechanisms, the special physics of the nanoworld -the constant shaking of Brownian motion and the universal stickiness that arises from the strength of surface forces -will present larger an larger obstacles that we will have to design around". 17 Nanodesign should be based on the principles used by cell biology, labeled "soft engineering". It should not "treat the special features of the nanoworld as problems to be overcome, instead it exploits them and indeed relies on them to work at all". 18 Given such differences, to what extent bio-inspiration may provide engineering principles? So striking is the contrast in Jones"s book that his notion of "machine" sounds odd. It conveys near-fantastic and surrealist images à la Dali. In the course of a discussion on this issue, Alfred Nordmann argued that Jones does not really provide an example of bio-inspired machine. He is not really concerned with technology. Nature provides an ideal that will never produce real machines but "phantom machines" -teleological ideals rather than technological solutions. However, soft engineering provides clues for highly "concrete technology" in the technical meaning of this term. The term "concretization" is used by Georges Simondon, a French philosopher of technology. 19 Concretization consists in turning obstacles into conditions. A concrete machine works precisely because of (and not despite) its association with a specific environment. The environment where the machine will operate is not an external feature or a simple parameter that engineers have to take into account in the design process. The milieu is not something to which the machine will have to be adapted; it is an intrinsic aspect of the design of the machine. This is the major lesson provided by biological processes of self-assembly. 20

Jean Marie Lehn who developed bio-inspired self-assembly strategies in supramolecular chemistry 21 moved on to a program of "dynamic combinatorial chemistry", which emphasizes another aspect of biomimetics. Lehn"s "Aufbau strategy" relies on the information stored at the molecular level. But information is processed through interactions between molecules. Self-assembly requires an "internal communication" between the components 22 , so to speak a society of molecules. "A glass of water is not like a water molecule", Lehn often says to stress that isolated molecules do not behave like interacting molecules. After inducing molecular recognition between artificial receptors and their substrates, the next step is to build up systems through the controlled self-assembly of supramolecular architectures. And the third step is to induce adaptation and evolution. Lehn"s dynamic combinatorial chemistry can be described as a program mimicking Darwinian evolution. The components mixed in a solution explore the possibilities of binding and this dynamics ends up with the correct double helix. Unlike the lock and key static model of recognition, which presupposes that the correct target has been identified, in this process the lock and the key select each other, through a random process of interactions. The basic concepts are "from static to dynamics, from real to virtual, 17 Ibid., p. 127 18 Ibid. 19 Simondon (1989) 20 Whether biological systems designed by Darwinian evolution are optimized or not is the matter of ongoing debates. S.J. Gould, R.C. Lewontin, (1979) For Jones biological systems are optimized and provide a norm rather than inspiration for nanotechnology. "The insights of molecular cell biology show us more and more clearly how optimised nature"s machines are for operation at the nanoscale. …] Nature has evolved to get nanotechnology right.(p.7) By contrast, Whitesides points out a major limit of bio-inspiration for self-assembly: biosystems do not make use of magnetic interactions which could prove very promising in technological systems because they are rather insensitive to environment. But here is precisely the key feature of self-assembly in biological systems. It is a process involving environment-sensitive properties, and responding to environmental changes.

21 Lehn (1995) 22 Lehn (2006) and from prefabricated to adaptive". 23 The solution in the vessel potentially contains all possible combinations between the components. Or to go back to the car metaphor, the box contains not just the parts of one car, but the parts of all possible cars (from 2 CV to Formule 1) and the output depends on mutual adaptation. This blind process is not unlike the process of creation of order out of chaos in ancient Greek atomistic cosmogonies. Lehn insists on the analogy with artistic creations in poetry and music such as Pierre Boulez"s combinatorial composition.24

Integration

Integrative technology is a program carried by Carlo Montemagno, an engineer and professor of Biomedical Engineering. 25 It combines both previous strategies since the purpose is to hybridize living and non-living systems, in order to make artificial devices mimicking membranes or muscles. Most research projects are oriented towards biomedical applications. They try to mimic the brain activity with artificial vesicles, with units performing a specific task. However the ambition is to create systems that offer emergent capabilities through extensive use of nature"s models of molecular interactions and supra molecular assemblies..« Integrative technology, the fusion of Nanotechnology Biotechnology and Information technology, provides the ability to build artificial organelles, functional units that manifest emergent properties that result from the stochastic non-linear interactions between the components of the system." 26 Membranes are key actors in this program, because of their multiple functions: they determine the spatial organization, supply electricity, sense and relay information, detect specific molecules. On this basis it is conceivable to engineer an artificial membrane that processes information in a biological sense, and responds to its environment. For instance, the project aimed at producing excitable vesicles is explicitly conceived as an illustration of the emergence of higher-order properties. 27 By incorporating ion channels into a biomimetic membrane the purpose is to make a responsive system that will generate ionic currents when stimulated. Then by treating each vesicle as a neuronal mode the next purpose is to engineer computational units. Systems of excitable vesicles should be capable of performing various functions of the brain. It would execute rapid and precise pattern recognition from incomplete data sets, and process information from different sources.

The integrative program is grounded on a specific view of living systems. They are complex machines made of simple molecular devices. The machine metaphor differs from the clockwork mechanism (Cartesian model) underlying the hybridization program previously described. The cell is a computer, an information processor, with a physical separation between the machinery (the metabolic processes) and the program (chromosomes). It is more like a Turing machine with algorithmic complexity. This model combining biochemistry with artificial intelligence and neuronal studies is widespread in the nanotechnology community as well as in synthetic biology communities.

It differs from the biomimetic model because of the lack of concern with interactions with the environment. Ironically the so-called "integrative technology" is not deeply concerned with how to integrate artifacts within biological environments. How to avoid adverse effects due to immune responses is not an issue. And the least concern is how to get the artifact to work together with the biological environment in order to make a "concrete machine". Integration is not an issue because the underlying assumption is that molecules, cells and neurons are of the same nature, they are all computer-like.

To sum up this section, the three types of self-assembly programs here outlined are based on quite different views of nature. In the hybridization program (N°1), living systems are collections of independent devices that can be put at work in artificial machines like mechanisms assembled in a clock. Hybridization is a strategy inviting a process of fabrication.

It requires both a designer -a clockmaker who designs an overall project or a player who has the whole picture of the jigsaw puzzleand a strict control of the process. In the integrative program (N°3) there is also a designer although the project is to build a system that manifests functionality not constitutive of its components, with emerging properties. By contrast, biomimetic self-assembly (program N°2) is a blind process of creation through combinations and selection without external designer. Although chemists often use the paradoxical phrase "we self-assemble molecules", the process is going on without human involvement. The subject "we" just initiates the process of self-assembly by securing the necessary agencies and appropriate conditions. One would hardly dare say that they "engineer" structures or machines whereas Montemagno can be adequately presented as a "medical engineer". Such opposite views get with alternative technological styles. For chemists such as Whitesides and Lehn, self-assembly may not be a key for nanotechnology. Whitesides insists that self-assembly is not confined to the molecular level and noted that biological structures are relatively large compared to the devices designed in nanoelectronics or nano-optics. 28 . He even stated that self-assembly is more suitable and more promising at the mesoscale. 29 Lehn is even more radical in divorcing self-assembly from nanotechnlogy. For him selfassembly and dynamic combinatorial chemistry offer an alternative to nanotechnology attempts at working with individual and isolated molecules.30

II. Towards a molecular vitalism?

The current concern with self-assembly is more than a convenient process for engineering at the nanoscale where human intervention is no longer feasible. Beyond the technological or medical purposes driving most research programs, self-assembly revives a traditional metaphysical issue concerning the distinction between living and non-living systems. Vitalism that one could regard as an obsolete topic tends to become a hot issue again. In June 2007 the editorial of a special issue of the journal Nature devoted to synthetic biology was entitled: "Synthetic biology provides a welcome antidote to chronic vitalism". More seriously three biologists Kirschner, Gerhart and Mitchison devoted an important paper to conceptual issues entitled "Molecular vitalism".

A Strategic Distinction

Without questioning the importance of genetics and genomics Kirschner, Gerhart, Mitchison campaign against the reductionism embedded in molecular biology and raise the question "to what extent the postgenomic view of modern biology would convince a nineteenth-century vitalist that the nature of life is now understood". 31 They focus on the distinction between self-assembly and self-organization. Self-assembly is defined in thermodynamic terms as a system reaching a state of equilibrium, a state of minimum free energy. Self-organization requires two additional conditions: i) a capacity for unitary organization (polarization), ii) a capacity for to regenerate a regular structure when the components are altered (regulation). In their view self-assembly is a doctrine, "an extension of the central dogma of molecular biology bringing us from the realm of linear information to the real of protein assemblies". 32 By contrast self-organization is observable in organisms or embryos rather than in machines, it marks the divide between art and nature.

It is thus clear that the distinction between self-assembly and self-organization becomes strategic when the issue of the nature of life is raised. Kirshner, Gerhart and Mitchison"s distinction can be justified at the conceptual level. Self-assemblya recent term that emerged in organic chemistry and Materials Science in the 1980s -supports a mechanistic view of life as the notion of assembly connotes technology (assembly line). By contrast the term selforganization was introduced in the late eighteenth-century by Immanuel Kant to mark the distinctive features of organisms. The notion of self-organization resurfaced in the 1970s in two different contexts, cybernetics (in particular John Foester"s Biological Computer Laboratory created in 1958) and physical chemistry (Ilia Prigogine"s work). Its meaning became closer to the current definition of self-assembly. 33 For Prigogine self-organization is evolution toward steady-states, which means that self-organized systems are open systems. In fact, according to Stengers, Prigogine took his notion of self-organization from embryologists who used this term in response to the failure of attempts at identifying a specific chemical substance that would induce the process of organization in early embryos. His ambition was to reconcile the biological order with the second principle of thermodynamics by introducing the time arrow in physics. 34 For John Von Foerster, self-organization means order from noise with decrease of relative entropy, and increase of redundancy within the system. Henri Atlan"s publication L'organisation biologique et la théorie de l'information in 1972 retained the view of self-organization as order from noise. However he emphasized that it was complexity from noise. In his view based on Shannon"s information theory, self-organization is a process requiring a hierarchical multilevel system and initial redundancy, so that it leads to a decrease of redundancy. Like Kirshner, Gerhart and Mitchison, Atlan insisted on the originality of self-organization, by stressing the contrasts between biology and human technologies. Noise, a major obstacle for engineering projects is the condition for generating order in "natural machines". Living organisms turn our major obstacles into operating conditions. 35 "Noise, for the former [communication engineers] is a bitter pill, for the latter [biology] it is the spice of life. Redundancy for communication engineers is a burden. It is a bonus for biologists". 36 Atlan characterized self-organization by its creative power. On the basis of a study of immune systems, he argues that self-organization is more than a creation of information out of noise it also creates "meaning". The discrimination between self-and notself is not just a deterministic reflex programmed in the genes. It is described as the result of "a dynamic process of continuing challenges and responses". 37 Thus selforganization becomes a process of individuation, which is radically different from selfassembly. Self-assembly may result in the production of aggregates but it will never generate an individual unit, since for Atlan the individual is not a product of some obscure mechanism, 32 Ibid. p. 80 33 Stengers (1985) 34 Stengers (1985) p. 36 35 Atlan H, (1972) and[START_REF] Atlan | Entre le cristal et la fumée[END_REF] 36 Atlan H, Cohen I.R., 2006, p. 125. 37 Ibid., p. 137 it is the process itself of interactions with a unique environment.

Alternative metaphysical agendas

To what extent research programs focused on self-assembly, revive the ambition to provide physical-chemical accounts for the emergence of life or defend the alternative vitalistic position through a clear-cut distinction between self-assembly and self-organization? To answer the question requires a more precise view of the relation between scientific research programs and metaphysical views. In the first section I tried to dig out the tacit metaphysical assumptions underlying research practices. Here I will focus on the metaphysical agendas that a number of scientists explicitly state in their publications. Such metaphysical claims proliferate on the margins of research papers, in commentaries, in semi-popular articles or in blogs, and they often belong to the regime of promises. In fact similar scientific practices and metaphysical views can lead to divergent metaphysical agendas.

For instance, a clear-cut distinction between self-assembly and self-organization is strongly recommended by Richard Jones. "People use different definitions, but it seems to me that it makes lots of sense to reserve the term self-assembly for equilibrium situations.

[…] We can then reserve selforganization as a term for those types of pattern forming system, which are driven by a constant input of energy. A simple prototype from physics are the well-defined convection cells you get if you heat a fluid from below, while in chemistry there are the beautiful patterns you get from systems that combine some rather special non-linear chemical kinetics with slow diffusion -the Belousov-Zhabotinsky reaction being the most famous example. " 38 Jones relies on the thermodynamic notion of self-assembly as the minimization of free energy in a closed system, which leads to equilibrium state. For instance, phospholipids with hydrophobic and hydrophilic ends placed in aqueous solution spontaneously form a stable structure. Self-organization only occurs far from equilibrium, in open systems, as it requires external energy source. It is a production of order out of irreversible process with energy dissipation. It is a local phenomenon illustrating the significance of singularities, out of the scope of statistical mechanics.

By contrast, George Whitesides does not care for any distinction between self-assembly and self-organization. He rather defines two types of self-assembly: the static one -resulting in equilibrium state-and the dynamical one, with energy dissipation. 39 Dissipative structures are thus given as examples of self-assembly. This is all the most striking that Whitesides deplores the current abuse of the term self-assembly and tries to provide a more focused definition: ""Self-assembly" is not a formalized subject, and definitions of the term "self-assembly" seem to be limitlessly elastic. As a result, the term has been overused to the point of cliche´. Processes ranging from the non-covalent association of organic molecules in solution to the growth of semiconductor quantum dots on solid substrates have been called self-assembly. Here, we limit the term to processes that involve pre-existing components (separate or distinct parts of a disordered structure) are reversible, and can be controlled by proper design of the components. "Self-assembly" is thus not synonymous with "formation." 40 Despite his efforts to limit the notion Whitesides"s definition embraces a wide variety of processes ranging from crystallization on surfaces, templated synthesis to cell"s functions and schools of fish. Thus Whitesides extends the realm of self-assembly to all length-scales from atoms to galaxies via 38 Softmachine blog, Nov 15 2005 http://www.softmachines.org/wordpress/?m=200511 39 Whitesides, Grzybovski (2002) 40 Whitesides, Grzybovski (2002) p.2418. biology. 41 Far from confining self-assembly to the nanoscale, Whitesides and his collaborators argue that self-assembly works at all scales and that its future lies primarily at the mesocale. 42 Lehn uses both terms more or less interchangeably to characterize the synthesis of supramolecular architectures. He just assumes that self-organization is self-assembly with the production of a precise structuresuch as double-helix metal complexes and pentagonal or hexagonal grids, depending on the nature of the metallic ion used. He insists on interactions between molecules and their collective behavior. Considering that isolated molecules do not behave like interacting molecules, that a glass of water is different from of water molecule, Lehn assumes that something emerges from their "being together". Togetherness was precisely one major feature of Prigogine"s notion of self-organization according to Isabelle Stengers. It implies not only "being together" but "acting together", a collective behavior which results from coupling processes rather than just expressing information contained in the components. Thus for Lehn, controlling the basic forces of self-organization is the ultimate aim of chemistry.

Indeed one may ask: Does it really matter whether dissipative structures are viewed as a variety of self-assembly or as a variety of self-organization? Who cares for the multiple meanings and different extensions of the notions of self-organization and self-assembly? In most natural sciences, definitions are a matter of convention, and sometimes a matter of convenience. Loose boundaries occasionally proved fruitful to the advancement of science. Moreover they testify to the fact that this concept is very successful. From the point of view of the dynamic of knowledge, Sabine Maasen argues that "the price of a term being successful is its increasing vaguenessand the perceived need for each individual field of research to define (and hence limit) its use." 43

Science War ?

Such distinctions are strategic for delineating territories between rival paradigms. It has to do with the demarcation between the respective territories of chemistry and biology. Jones"s criteria of demarcation based on equilibrium and far from equilibrium draws a clear-cut boundary assigning self-assembly to physicists and chemists while self-organization remains the major feature of life. "Self-assembly is not in itself biology, it is used by biology. A system organized by equilibrium self-assembly is moving toward equilibrium and things at equilibrium are dead." 44 Jones claims that although information stored in the sequence of amino-acids accounts for protein folding, life is more than just information; it is also metabolisms. Nevertheless the physicist"s approach is relevant to increase our understanding of biological systems in so far as life is not an isolated system and complies with thermodynamics second law. By contrast, Whitesides"s strategy of expanding the domain of self-assembly is in keeping with his belief that chemistry is everywhere and must go everywhere. 45 Chemistry so far confined to the interactions between atoms and molecules using strong covalent bonds is expanding its territory, by using the whole spectrum of weak forces and operating at various scales. Chemical language can decipher the most complex phenomena: "The nature of the cells is an entirely molecular problem. It has nothing to do with biology". 46 And since 41 see Table 1 in Whitesides, Grzybovski (2002) 42 Whitesides, Boncheva, 2002. 43 Maasen, 2006 44 Jones, softmachines blog, March,14, 06 How much should we worry about bioNT ? 45 Whitesides, 2004. 46 Whitesides quoted by Philip Ball (2006) p. 501. neurons also use chemical mediators, chemists should also contribute to merge silicon electronics with the brain. Similarly Lehn"s program of Constitutional Dynamical Chemistry revives the greatest ambitions for chemistry. His program evolving from supramolecular chemistry to dynamic combinatorial chemistry looks like a modern replica of Berthelot"s grandiose program of synthetic chemistry, which would gradually lead him, step by step, to more and more complex compounds and ultimately to the frontiers of life. 47 Lehn portrays chemistry as the "science of informed matter", a core science mediating inanimate matter (materials process) and animate matter (living organisms and their complex behaviors). 48 Self-assembly has revived the chemists" ambition to access the "essence of life". As Philip Ball rightly points out, chemists are now addressing the "big questions" about the Big Bang and the origin of life. Far from confining their work to the production of utilities, chemists want to address questions about the origin of life and of consciousness: "For me, Lehn says, chemistry has a most important contribution to make to the biggest question of all: how does self-organization arise and how does it lead to the Universe to generate an entity that is able to reflect on its own origin?" 49 To an outside observer, this expansionist attitude strikes as being at odds with the current consensus about the merits of cross-boundary research and interdisciplinary programs. How is it possible to hear such passionate advocates of a discipline when the leaders of the program Converging Technologies announce that the age of scientific specialties is over:

"The sciences have reached a watershed at which they must unify if they are to continue to advance rapidly. Convergence of the sciences can initiate a new renaissance, embodying a holistic view of technology based on transformative tools, the mathematics of complex systems, and unified cause-and-effect understanding of the physical world from the nanoscale to the planetary scale." 50 Although interdisciplinary teams and cross-boundary research programs are flourishing and have demonstrated their efficiency on some occasions, it seems that the grand unifying understanding of the world is neither for today, nor for tomorrow… unless unifying means reducing everything to atoms and molecules.

A common plea against reductionnism

The current focus on self-assembly did re-open the debate over vitalism but it would be oversimplistic to conclude that the fireline between the advocates of vitalism and advocates of mechanism follows disciplinary boundaries. The map of the battlefield is more complex. The fireline has significantly shifted. It is no longer a matter of disciplinary affiliation because the distinction between living and non-living does not really make sense at the nanoscale. In fact, in various scientific communities -physics, chemistry, biology, artificial life, etc -a number of individual scientists are using self-assembly or self-organization as watchwords against reductionism. Both Whitesides and Lehn claim that their views of chemistry are not reductionist. Lehn insists that it is chemistry, which is becoming complex, adaptive and evolutive. Whitesides claims that chemistry so far was « blindly reductionist » and that chemists will have to move 47 See Bensaude-Vincent & Stengers (1996) p. 152-154 48 See Lehn (2002) 49 Lehn quoted by Ball (2006) p. 501. 50 Roco, Bainbridge (2002) p. xii « beyond molecules to learn the entire problem ».51 Just as Prigogine"s ambition was not to reduce biological systems to physics or chemistry, both of them assume that chemistry has the power to explain living systems because chemistry in turn is deeply transformed by its application to complex phenomena. Just as Prigogine imported in physics the problem of collective behavior or « how to act together » that had been raised by embryologists in their use of the term self-organization, 52 Lehn is importing the same problem at the molecular level. In plagiarizing Feynman"s too famous phrase one could say: there is plenty of room for complexity at the bottom, if you look carefully at the collective behavior of molecules! To a certain extent biologists such as Kirshner, Gerhart and Mitchison agree with the chemist Jean-Maris Lehn on this point. They assume a continuity between self-assembly and selforganization for a single cell. At the level of one single cell, self-organization is just an extension of self-assembly employing chemical strategies in order to break symmetry. The formation of ordered aggregates by the self-assembly of identical components generates an asymmetry and leads to polarization. So polarization and regulationthe two distinctive features of self-organization in single cellsmay be viewed as simple extensions of selfassembly. By contrast, when self-organization occurs at the system level (for instance in embryos) it is a quite different phenomenon. It involves exploration of an assembly landscape and selection of a functional steady-state. It implies a diversity of states offering possibilities for selection. Thus the dividing line no longer delineates chemistry from biology. Rather the contrast is between two alternative approaches to molecular phenomena: either considering single molecules or their collective behaviors. Kirshner, Gerhart, Mitchison claim that it is time to move beyond the genomic analysis of proteins and RNA components of the cell in order to understand the robustness of biosystems. Lehn claims that it is time to move to a dynamic combinatorial chemistry.

In conclusion, the current interest in self-assembly is not just born out of the bare necessity to explore a technique for making artifacts at the nanoscale level. It is also driven by big metaphysical issues concerning the nature of life. The ambition to account for the circumstances and mechanisms at work in the emergence of life underlies a number of research programs for directing the self-assembly of molecules. In this respect, the conceptual distinction between self-assembly and self-organization offers a strategic field for reigniting the debate betwen vitalism (stressing the difference between the organization of living systems and machines) and mechanism (stressing their analogy with the connotation of assembly line). However the contrast between assembly and organization no longer refers to the divide between chemistry and biology. It is not the continuation of the long tradition of the chemists conquistadores who pretended to be able to make life in a test-tube. Rather it is an urge to go beyond the current reductionism that characterizes the molecular approach to chemical and biological phenomena. The emphasis today is more on the prefix "self", than on the alternative assembly or organization. The prefix "self" may refer to diverging strategies of self-assembly as well as diverging metaphysical agendas. 53 In hybridization programs as well as in the so-called integrative approach, the "self" refers to a functional device, which is isolated as a separate part of a machine. The result is a logical machine embodied in a physical structure. By contrast in biomimetic strategies, "self" refers to a population of interconnected molecules exploring the various possibilities of collective behavior.

Table 1 : Self-Assembly occurrences in SCI & SSCI

 1

	1990	1995	2000	2005
	86	807	2444	5741

Table 2 What do they have in common? Machines and molecular machines

 2

		(From Zhang , 2003, p. 1174)
	Machines	Molecular machines
	Vehicles	Hemoglobin
	Assembly lines	Ribosomes
	Motors, generators	ATP synthases
	Train tracks	Actin filament network

Table 3 Contrasts between natural and artificial designs Living Systems Human technology

 3

	Ambient Temperature +	High temperatures (difference needed)
	Low energy (ATP)	High energy
	Mobility of the components	No or few fluctuations
	Brownian motion
	Order out of noise	Noise as nuisance
	Plasticity: conformation changes in response	Rigid components
	to environment
	Adhesive Surfaces (van deer Waals)	Separated Surfaces
	Variable number of components	Fixed number of components
	Instructions for assembly inherent in the	Instructions for assembly from outside
	components
	Local equilibrium between forces
	Correction through trials and errors	Central Control
	Robustness through stochasticity	Robustness through redundancy

  Table 3 on p. 2402.

[START_REF] Keren | DNA-templated carbon nanotube field-effect transistor[END_REF]

Steven Boxer (1991)

[START_REF] Jones | Soft Machines[END_REF]

Ibi. p. 86

[START_REF] Lehn | Dynamic combinatorial chemistry and virtual combinatorial libraries[END_REF].

[START_REF] Lehn | Entretien avec Jean-marie Lehn sur les possibles naturels en chimie[END_REF]

[START_REF] Montemagno | Nanomachines: A Roadmap for Realizing the Vision[END_REF]

Montemagno (2004) p. 39

[START_REF] Montemagno | eds The co-evolution of Human Potential and Converging technologies[END_REF]

[START_REF] Whitesides | The "right" size in nanobiotechnology[END_REF]Whitesides ( ) p. 1161. .

Whitesides, Boncheva (2004)

[START_REF] Lehn | Entretien avec Jean-marie Lehn sur les possibles naturels en chimie[END_REF]Lehn ( ) p. 2462. .

[START_REF] Kirschner | Molecular Vitalism[END_REF] p. 79

[START_REF] Whitesides | Taking chemistry in new directions[END_REF]

[START_REF] Stengers | Les généalogies de l"auto organisation[END_REF] p. 82

See Dupuy (2000)


B Bensaude
email: bernadette.bensaude-vincent@univ-paris1.fr

Keywords:

Synthetic biologists are extremely concerned with responsible research and innovation. This paper critically assesses their culture of responsibility. Their notion of responsibility has been so far focused on the identification of risks, and in their prudential attitude synthetic biologists consider that the major risks can be prevented with technological solutions. Therefore they are globally opposed to public interference or political regulations and tend to self-regulate by bringing a few social scientists or ethicists on board. This article emphasizes that ethics lies beyond prudence and requires a cultural evaluation of the modes of existence of the various microorganisms designed by synthetic biologists, independently of their potential applications.

It is now well established that the emergence of novel technologies such as nanotechnology, genomics, or synthetic biology raises ethical issues. As these technologies reengineer life and promise revolutionary applications, they also generate concerns and risks that have to be addressed upstream. Ethics is viewed as the ordinary companion of science and technology in contemporary risk societies [START_REF] Beck | Risk society: towards a new modernity[END_REF]. From the beginning, publicly funded research programs on synthetic biology have devoted a portion of their budgets to the study of potential ethical, legal, and societal impacts. The European EC-FP6 program funded SYNBIOSAFE, a project focused on the safety, security, and ethical aspects of synthetic biology (Schmidt et al. 2009). In the USA, the Synthetic Biology Engineering Research Center (SynBERC) brought together biologists, engineers, and humanities scholars to achieve its ambition of "making life easier to engineer." The community of synthetic biologists seems to be concerned with their responsibility as scientists. The international meetings launched in 2004 by the Biobricks Foundation include talks or even symposia on ethical and societal issues with the intention to "work together so that the ramifications of such efforts are most likely to benefit all people and the planet" (http://sb6.biobricks.org/about/). Although "profit" is not mentioned, it is clear that synthetic biology is part of the general commitment to "responsible research and innovation" that has been epitomized by three "P"s in a report to the European Commission:

"Responsible Research and Innovation as an outcome seeks to generate the 'right' end points which benefit people, planet and profit" (Sutcliffe 2011, p. 7).

What is the outcome of ten years of buzz and concern about responsibility in synthetic biology? What are the measures to regulate the development of synthetic life, to prevent potential disasters, and to engage the public in technological choices? An overall survey of what has been done over the past decade is much needed but it would be beyond the scope of this article. Its ambition is more modest. It first considers the purposes and commitments to responsible behavior in various reports and initiatives in Europe and the USA. The second section tries to clarify what responsibility means for synthetic biologists, policy makers, industrial managers, and civic associations. The third section will emphasize the limitations of current ethical perspectives. Finally the article broadens the spectrum of ethical issues that remain to be addressed and discussed in a public arena.

Will to Responsibility

Synthetic biology is a heterogeneous field with a variety of research agendas and visions of the future [START_REF] Deplazes | The ethics of synthetic biology: outlining the agenda[END_REF]. The modular approach of the Biobricks program differs from metabolic engineering, from the minimal genome approach, from in silico synthesis or computer modeling, and finally from the chemical synthesis of protocells. In turn they seem quite far from the ambitions of xenobiology aimed at the synthesis of alternative nucleic acids. It therefore comes as no surprise that synthetic biologists develop quite different views about their responsibility.

Also, not all countries are equally engaged in synthetic biology research and the accompanying programs about ethical, legal, and societal impacts (ELSI). In Europe, a comparative study shows that such programs are well funded and developed in the United Kingdom, while there is no real effort on ELSI issues in Switzerland and Netherlands (Pei et al. 2010). Even in the UK, ethical and societal issues are not the prime concern. In stark contrast to the 2004 report on nanotechnology by the Royal Society and the Royal Academy of Engineering (RAENG), which balanced challenges and opportunities, the report on synthetic biology published by the latter in 2009 is primarily focused on the potential competitive advantages generated by synthetic biology for the UK (RAENG 2009).

In France, the Parliamentary Office for the Evaluation of a very good job of identifying issues related to the method, applications, and distribution of synthetic biology. As it is assumed that synthetic biology does not raise novel ethical issues, the program resulted in a kind of checklist of standard issues such as biosafety, biosecurity, intellectual property, and social justice (Schmidt et al. 2009). This checklist of issues was later developed by the European Group on Ethics in Science and New Technologies to the European Commission (EGE) who "agreed that apart from safety issues associated with synthetic biology, an ethical, legal and political governance of synthetic biology is needed in the EU and worldwide to ensure that the interests of society are respected" (EGE 2011).

Who is in a position to clarify the interests of society? Over the past decade scientific journals have published many articles and special issues related to synthetic biology with occasional commentaries about ethical issues. However, the buzz about synthetic biology has not really penetrated the public sphere. Despite spectacular announcements and a number of articles on biohackers, the media coverage for synthetic biology has been rather modest. In 2010 a survey commissioned by the European Commission concluded that 17% of the European public is aware of the existence of synthetic biology (European Union 2010). Does this mean that there is no concern at all in the civil society? The Canadian activist nongovernmental organization (NGO) ETC Group issued three alarming reports on synthetic biology calling for a moratorium (ETC Group 2007[START_REF]Commodifying nature's last straw? Extreme genetic engineering and the post-petroleum sugar economy[END_REF], 2010). Nevertheless, over the first decade, synthetic biology prompted very few public debates or citizen conferences. Apart from the citizen juries organized in the UK and a 6-month public forum organized by the French civil society organization VivAgora in 2009, the subject is rarely brought into the public arena. There is no real dialogue with the society at large. Listening to the public might well slow down the pace of development that synthetic biologists want to maintain or accelerate. The conclusions of a public dialogue conducted in the UK together with 41 stakeholder interviews show that the promises of smart solutions to big issues such as renewable energy or medicines are not convincing enough to overcome all concerns. Significantly, the most serious concerns expressed in this dialogue are related to the motivations of scientists who, driven by their own research interests, might forget their responsibility [START_REF] Bhattachary | Synthetic biology dialogue[END_REF].

Nevertheless, the champions of synthetic biology in the USA did not forget their responsibility. They strive to behave as responsible engineers with regards to the products of their activity. In the series of international conferences Synthetic Biology x.0 organized by the Biobricks Foundation, ethical issues are an integral part of the programs. The first meeting in June 2004 closed with a plenary lecture delivered by Paul Rabinow, a famous anthropologist at Berkeley [START_REF] Rabinow | Assembling ethics in an ecology of ignorance[END_REF]). The second meeting, held at Berkeley in 2006, dedicated a third day to four key societal issues: biosecurity and risks, public understanding and perception, ownership and sharing, and community organization. The third conference in Zurich had a few parallel sessions on ethics. At the Synthetic Biology 4.0 meeting in Hong Kong (2008), ETC Group hosted a panel session on global societal impacts. At the same time the gene companies grouped in an International Association of Synthetic Biology started negotiations to set up a universal code of conduct for screening orders [START_REF] Maurer | Synthetic biology marketplace: screening out terrorists[END_REF]. At Synthetic Biology 5.0 at Stanford in July 2011, a poster session was arranged on "interacting with the world" (including risks, environmental, ethical, legal, societal, and philosophical issues). And SB 6.0, held at Imperial College in London in July 2013, called for papers on environmental and societal issues. This thematic organization emphasizes the concern with broader societal issues, and at the same time is reminiscent of the old divide between humanities and natural sciences.

Thorough attempts at moving beyond the too famous divide between the two cultures are nevertheless noticeable. Social scientists have been invited to work closely with synthetic biologists, on a daily basis. In a number of research projects, humanity scholars have been "embedded." For instance, the Paris Team in the 2009 iGEM competition was awarded a prize for the ethical and sociological analysis included in the project [START_REF] Aguiton | SynthEthics: an ethical and sociological analysis on synthetic biology[END_REF].

However, the junior scholar who was publicly celebrated during the jamboree in Boston had been in agony during the six previous months spent on the research team. She had been ignored, ostracized by the young science students who worked enthusiastically to prepare their biological part for the international competition. A more substantial commitment to ethics was the appointment of two senior Sharing information and materials is viewed as a precondition for the success of synthetic biology because patents increase the costs of research to such a point that they become an obstacle to further developments. For Rob Carlson, the open source paradigm is necessary for a rapid increase of users of synthetic biology that will bring cost reduction and secure the commercial future of synthetic biology [START_REF] Carlson | Biology is technology: the promise, peril and new business of engineering life[END_REF]). Carlson's plea for open source is not based on moral injunctions; rather, it goes hand in hand with epistemological and political recommendations. Carlson favors the strategy of chassis over synthetic genomics as the most promising approach because it reduces complexity (Carlson 2010, p. 102). Accelerating innovation in biotechnology requires molecules that behave in understandable and predictable ways, for simulation and standardization purposes.

Along with his epistemological choice of reductionism, Carlson presents the political options required for the successful development of synthetic biology. He vehemently advocates a free and deregulated market for synthetic biology, arguing that regulations are always leaky and inefficient. He refers to the ban on illicit drugs and concludes that "where there is a market, there will always be attempts to supply it" (Carlson 2010, p. 123).

From the moral notion of responsibility, which implies obligations and the commitment to respond for one's actions, what is retained? Since "ethical responses do not pre-exist the questions that elicit them" [START_REF] Dupuy | Ethics beyond prudence: towards a normative assessment of nanotechnology[END_REF], what are the questions that prompt ethical concerns among synthetic biologists? The ethical debates in the series of SB conferences are essentially about risk issues. From the outset, biosecurity came up as the major concern: as synthetic biology can synthesize pathogen viruses it can be misused to make more effective bioweapons. The risk of bioterrorism is enhanced since artificial DNA can be purchased on the Internet.

Stephen Maurer, a lawyer at Berkeley, outlined a code of conduct for protecting the public from the risks of bioterrorism, which relied on the capacity of gene companies to screen orders and on the scientific will and commitment for the field to regulate itself. 2 However, it is worth mentioning that some synthetic biologists consider the Biobricks program more as a tool to bring students in contact with the field, through the iGEM competition, rather than as a serious program of engineering.

dependent on a specific artificial nutriment that cannot be found in nature. A third measure to prevent interplays with the environment is to engineer organisms with a genetic code that is not readable by ordinary DNA-based organisms. Thus, the attempts at synthesizing unnatural nucleic acids such as XNA are being justified as measures of prudence [START_REF] Schmidt | Synthetic constructs in/for the environment: managing the interplay between natural and engineered biology[END_REF].

Finally, issues of social justice have been so far addressed in terms of access to and distribution of synthetic biology resources.

It is all about enabling innovative developments of synthetic biology through open access and preventing the enhancement of the global divide through an international dialogue. Never is there a hint that synthetic biology and other so called "technological fixes" could be one more alibi to avoid facing the world we have made through previous generations of technology. Rather than confront the underlying problems of over-consumption and waste, synthetic biology is promoted as a "remediation"--a means to "medicate" a solution for the earth.

Beyond Risks and Impacts, What Kind of Governance

Therefore, the kind of responsibility developed in an ELSI framework can hardly be considered as a true ethical attitude. It certainly fits in ethical theories that judge the rightness of actions based on the intentions of the moral agents. But good intentions do not guarantee responsible behavior. "Responsible scientists" motivated by the best intentions in the world might unwittingly turn into irresponsible citizens who shape unsustainable futures.

Although anticipating impacts is looking at the consequences of actions, ELSI research cannot be considered as an instantiation of consequentialism. This specific ethical theory judging the wrongness and the rightness of actions on the basis of their consequences (rather than on the intentions of the agent or the action itself) would require taking into account the contingency of the future.

Instead of making decisions on the basis of calculable risks, a consequentialist has to take into account what we do not know, i.e., the ignorance generated by increasing knowledge, the scientific uncertainty embedded in synthetic biology. In consequentialism, the responsibility for the consequences has to be extended to the realm of "moral luck" when the course of the action to be judged depends on factors beyond the control of the moral agent [START_REF] Williams | Moral luck[END_REF].

The major limitation of the programs of anticipatory governance of risks in synthetic biology is that they simply overlook or even deny uncertainty. They rest on a blind adhesion to the reductionist manifesto of the Biobricks Foundation, assuming that human-designed, standardized, and well-characterized biological parts assembled into modules will be entirely predictable and that the synthetic organism will not have any emergent properties. Despite the doubts about the feasibility of this program, despite repeated attempts by experts to emphasize the radical uncertainty lying in synthetic biology [START_REF] Rodemeyer | New life, old bottles: regulating the first generation products of synthetic biology[END_REF])ethical and regulatory measures still rest on overconfidence in the control of synthetic microorganisms and deal almost exclusively with risks. In particular, the 2011 report of "BIOS," the research program conducted by the Centre for Synthetic Biology Innovation at Imperial College on synthetic biology, refers to Sheila Jasanoff's notion of "technology of hubris" to characterize the over-reliance on scientific evidence and systematically downplays the uncertainties [START_REF] Jasanoff | Technologies of humility: itizen participation in governing science[END_REF]Zhang et al. 2011, p. 16). The authors of the report propose to move from "scientifically informed bureaucracy" to "artistic governance." In the face of scientific uncertainty, in the face of the variety of actors involved in synthetic biology and the variety of scientific, industrial, and geopolitic interests at stake, the most effective governance consists in a continuous provocation of reflexivity among stakeholders rather than in a rigid regulatory regime.

Thus self-regulation, risk assessment and evidence-based policy have shown their limits. It is time to counterbalance the temptation to leave the governance of synthetic biology to a few dozen experts and let them decide if and how it should be regulated.

Of Microbes and Men

If we are to open up the field instead of closing it up on risk issues, and to develop an "art of governance," on which basis can we appraise synthetic biology? First of all, it is important to try to disentangle the valuations underlying the design of biological artifacts, to clarify them in order to submit them to open debates.

Anticipating the impacts that could be made by the products of genetic engineering is certainly a useful and proactive attitude.

But the process of design in itself is value sensitive, especially when it comes to designing life.

Whatever the purposes of their designers, anthropological meanings are embedded in biological artifacts together with deep cultural, albeit tacit, valuations. Using John Dewey's conceptual distinction between valuations and evaluations [START_REF] Dewey | Theory of valuation[END_REF][START_REF] Vincent | Ethique des nanotechnologies[END_REF], this section aims to clarify the spontaneous and intuitive assessments (valuations) in order to foster reflexive judgments (evaluations).

For this purpose, it seems better to proceed bottom-up, from the objects designed in synthetic biology up to their moral significance, rather than top-down from the perspectives of ethical doctrines. In liberal states, the governance of synthetic biology cannot be built on the basis of a privileged moral doctrine. Moral choices belong to the private sphere and cannot determine public or legal actions, whereas the government is expected to engage in the defense of core moral views such as humanity and nature.

Even though Rabinow and Bennet failed to convince their scientific partners that they had to collaborate in order to construct an appropriate ethical framework, their central question remains to be addressed: to what extent do the objects designed by synthetic biologists question the definition of what it means to be human? Synthetic biologists create new objects, they refurbish the world with human-designed entities that are supposed to perform desired functions and self-reproduce without interfering with their environment. The mode of existence of the objects designed in synthetic biology laboratories at the borderline between the natural and the artificial, between the living and the non-living, inevitably questions the grand divides that are the backbones of modern Western culture. They raise issues about the place and role of humans in nature, their relations to animal life, and to the environment in general.

The cultural evaluation of such value-sensitive objects of design cannot be conducted on synthetic biology in general.

Distinctions have to be made between the various kinds of objects designed under the umbrella of synthetic biology. Such distinctions should not be based primarily on the potential adverse effects that synthetic organisms could have-risk issues are only a minor component of the defense of core values--but will rather be based on their modes of existence.

Are biosynthetic objects natural or artificial? In "essence" synthetic biology is about redesigning and reengineering life. Its products are hybrids of natural objects and artifacts. But all products of human technology are also hybrids, as Descartes already argued against the ontological divide maintained by scholastic philosophers between nature and artifice 3 . Like Descartes, and his contemporaries, synthetic biologists value the products of their design for two major reasons: artifacts are useful for cognitive purposes as well as for increasing human health and wealth. Their insistence on quoting Richard Feynman's alleged saying--"What I cannot create I do not understand"--or Steven Benner's emphasis on synthesis as being the best way to test hypotheses (Benner et al. 2011) suggests that knowing through making is a major justification of synthetic biology. Social utility is even more valued, at least in the public discourses promising environmental and heath benefits.

It thus seems that the ambition to design and control living organisms is in keeping with the humanistic ideal of modernity.

Synthetic biologists still consider it their duty "de se rendre comme maître et possesseur de la nature," to place humans above all other animal species. They feel free to use living beings (whether 3 Descartes: "I don't recognize any difference between artefacts and natural bodies except that artefacts mostly work through mechanisms that are big enough to be easily perceivable by the senses (they have to be, if humans are to be able to manufacture them!)" (Principles of Philosophy, 1644, Section 4, § 203).

plants or animals) in their service. 4 Synthetic biology is thus valued as the continuation of the long-term process of emancipation from nature, equaled with civilization. Far from being a philosophical watershed, it reaffirms that humans are in command of nature. This anthropocentric perspective justifies the serene response of the Vatican to Craig Venter's announcement of the creation of a synthetic bacterium. As long as synthetic biology is not creating life de novo, and is working for the benefit of humanity, anthropocentric ethics is safe.

However this anthropocentric perspective can be challenged from two alternative perspectives: Is it possible to countervalue synthetic organisms as "works," as products of engineering? Is it possible to countervalue them as living beings?

While nature remains a core value in our culture, artifacts also have their cultural dignity. They can be valued either as expressions of human creativity or as technical objects operating and enduring in the world. Do synthetic biologists praise technology? A striking feature of Craig Venter's public presentation of his synthetic bacteria significantly named Mycoplasma laboratorium in 2010 is that he did not say a word about the engineering skills and the tour de force needed to implement a synthetic genome into the cell machinery of a neighboring Mycoplasma. Far from valuing the technicalities of this achievement he claimed: "This is the first self-replicating cell we've had on the planet whose parent is a computer" (USA Today 5/20/2010).

Digital culture and design seem more highly valued among synthetic biologists than technicality. Technicality as a mode of existence has been highly valued by the French philosopher Gilbert Simondon.

In his view, a concrete technical object is not the implementation of a design project into the physical world. Nor is it the assembly of individual parts with each part performing a specific function. Such abstract and "hypertelic" constructions signal artificiality rather than technicality (Simondon 1989, p. 47). By contrast, technical objects come into existence through a process of individuation, including the "milieu" into their operating scheme, just as natural objects. The process of individuation is neither the juxtaposition of fixed individual functions, nor a subjection of nature to human interests. Are there any hints of valuation of technicality in synthetic biology? Clearly the objects designed in the Biobricks program are all but concrete technical objects [START_REF] Kogge | Synthetic biology and its alternatives: Descartes, Kant and the idea of engineering biological machines[END_REF]. They are only individual parts, designed for performing a specific function waiting to be assembled in modules, that will still remain parts because no concrete entity can result from this process of Lego construction. As objects modeled on software engineering they are algorithmic machines rather than individual objects analogous to natural objects.

The objects designed in the branch known as xenobiology are presented as unnatural or "orthogonal" even when they are designed as "analogs" of natural nucleic acids. Most of them are abstract objects--in Simondon's sense--because they are designed for avoiding interactions with natural DNA in order to prevent risks [START_REF] Marlière | The farther, the safer: a manifesto for securely navigating synthetic species away from the old living world[END_REF]. Like soil-less cultures they are designed to operate offground, independently from the cell's natural environment. They are deprived of autonomy, and of the mobility and capacity to enter into new associations with their "milieu". As products of human design, they are neither the outcomes of contingent history like living beings, nor the outcomes of a process of individuation as concrete technical objects. They ignore the interdependency of individuals with their environment as well as the interdependency of present, past, and future, which characterize the mode of existence of natural and technical objects. As long as containment is the major concern of synthetic biologists, the problem of coexistence and synergies between synthetic organisms and natural organisms, which have acquired evolutionary capacities through billions of years, cannot be addressed. Therefore, such biosynthetic objects share no community of interests with living beings. There is no way for them to participate in a common world. They are from nowhere, from no time. They belong to the kingdom of utopia and uchronia but they do not acquire the cultural dignity of technical objects.

What about yeasts and bacteria engineered or reengineered for synthesizing precursors of drugs or of biofuels? They only exist as instruments of production in a laboratory or a factory. They are production tools confined in spaces under control, as generations of microorganisms have been used in the manufacture of beer, wine, yoghurts over the past centuries. They have to be stabilized and standardized for entering into large-scale industrial production.

From a biocentric perspective is it right to conceive living entities as machines performing functions for humans, to reduce them to chassis that can be functionalized in our service? Whatever their degree of artificiality synthetic organisms are living beings. As such they have an intrinsic value. For instance, the oncomouse designed in a Harvard laboratory for use as a research tool, which became a patentable invention and a commercial entity, has been depicted by Donna Haraway as a mouse that suffers so that we may live [START_REF] Haraway | Modest_Witness@Second_Millennium. FemaleMan_Meets_OncoMouse: feminism and technoscience[END_REF]. This transgenic and human-designed object nevertheless raises compassion and solidarity. Indeed, the organisms engineered by synthetic biologists are not like suffering animals. They are hardly considered as living beings deserving our respect. As heirs of two centuries of hygienist medicine even biocentric ethicists are more inclined to consider microbes as enemies rather than as moral subjects. Yet this spontaneous valuation may quickly change if we consider with the symbiotic relations between microbes and men. The thousand different species of commensal microorganisms associated with human bodies which form a complex ecosystem are highly valued by synthetic biologists who consider that thanks to their social interactions these microbes could be excellent vectors for deploying synthetic genetic circuits (Warren et al. 2011). If we accept that we are in a relation of mutual dependence with microbes we can no longer deal with them as simple means towards our ends. They rather can be seen as co-operators. Even though they may not suffer and raise empathy, they deserve care and assistance like domesticated animals, which have shared human lives through many centuries.

More precisely, it is the reductionist concept of life underlying the project of designing synthetic organisms that is questionable from an ethical perspective. The Biobricks program, for instance, is typically framed along a Cartesian view. Living systems are made of functional parts that can be assembled into a machine like a watch. This mechanistic concept of life supports a project of exploitation. As George Canguilhem convincingly argued, the Cartesian theory of animals-machines conveniently supported the project of using them as machines in the service of men [START_REF] Canguilhem | Machine et organisme[END_REF]. In stark contrast, Kant's comparison between mechanical machines (watch) and organic bodies (tree) emphasized the distinctive value of organized bodies. Unlike mechanical machines which have a "motive power," organisms have a "formative power." They self-reproduce, they maintain themselves. Their parts exist in relation to each other and to the whole, they are not designed by a clockmaker in accordance with a project. In this view living entities are an end in themselves and should not be used as machinetools for heteronomous ends.

In conclusion, it is clear that the "responsibility" promoted by the synthetic biology community is far from satisfactory for addressing the ethical issues raised by this emerging technology.

Without questioning the good intentions of synthetic biologists, the strategies developed to address ethical issues suggest a strong rejection of public interference or intervention in their turf.

Moreover, the focus on risk issues encourage the belief that societal and environmental problems are amenable to technological solutions. The governance of uncertainties requires broadening the interface between scientists working in the field of synthetic biology and the civil society. If the objects designed by synthetic biologists are to be parts of our common world, they have to be evaluated from an ethical and a political perspective.

  anthropologists in the program of the consortium SYNBERC in 2006. A permanent section entitled "Human Practices" headed by Paul Rabinow and Gaymon Bennett was created and generously funded. The two social scientists were to follow the local daily research pathway of synthetic biologists. They deliberately discarded the conventional position of bioethicists speaking from an outsider's perspective and made efforts to calibrate ethics to the actual research conducted in the consortium rather than to what was imagined or promised. They consequently determined to observe the researchers, to participate in the weekly laboratory meetings rather than taking the futuristic visions developed in public discourses. However, this attempt at integrating ethics as a major component of research projects endedin 2012 as the protagonists failed to engage in collaboration. This "anthropological experiment"--as Rabinow and Bennet name it--has been rejected by the leaders of the project (Rabinow and Bennet 2012). In Year 5 of the project the Human Practices division was accused of doing only observation. Rabinow and Bennet were criticized and resigned. The division is now reconfigured as "Practices" and focused on issues of risks. Ethicists on board had to comply with the expectation of the synthetic biologists rather than developing their own research interests. This quick survey of various sites where ethical issues about synthetic biology are addressed suggests that ethics has been dominated by synthetic biologists who frame the relevant issues and hire social scientists to support and secure the advancement of their research projects. Despite the European urging for a multistakeholder governance, despite the strong recommendations of the SYNbiosafe project, few citizens have been engaged in a dialogue and public interventions are not welcome. Synthetic biology revives the ideal of self-regulation discussed in the early time of genetic engineering, at the Asilomar Conference in 1975 (Cameron and Caplan 2009). How Has Responsibility Been Framed? In their effort to pursue the Asilomar ideal of self-regulation, the community of the Biobricks Foundation has developed an ethos based on openness and transparency. They invite amateurs' practice and promote garage or DIY biology. They encourage young talents to participate in the construction of the Registry of Standardized Bioparts through the international annual competition iGEM. In thus challenging the established hierarchies of academics, they champion a democratization of scientific practice. They promote a new model of scientific sociability open to amateurs, based on enthusiasm and creativity. In addition, they are opposed to the regime of intellectual property in biotechnology and are working hard to initiate a regime of open biology, inspired by the movement of open access in computer engineering (Calvert 2012; Hilgartner 2012). The Biobricks Foundation has implemented a legal framework to ensure free and open access to the standard Biobricks collected at the MIT Repository of Standard Biological Parts. The aim is to develop open technical standards to characterize the Biobricks and to provide educational support to allow the public to use and improve the Biobricks.

  This proposal raised controversy and 35 NGOs including ETC Group, GeneWatch, and Greenpeace, protested and urged to open a public debate on synthetic biology[START_REF] Aldhous | Synthetic biologists reject controversial guidelines[END_REF].Biosafety is also a major concern. Significantly, in Europe the ethical agenda of synthetic biology has been set up in the program entitled SYNbiosafe. Although the outline of the project distinguished three categories of issues--method-related, application-related, and distribution related (Desplazes et al 2009)--there is a striking imbalance in the treatment of each category. Application-related issues have attracted most of the attention. The ethical awareness is most often limited to risk issues, thus reducing ethics to a form of prudence. 1 Thus the culture of responsibility developed in the synbio community is more or less reduced to accountability. This term derived from book keeping denotes impersonal numbers, standardized rules, and procedures.In most countries, ethical discussions on synthetic biology revolve around risk issues and result in a list of standard issues to be addressed: biosecurity, biosafety, biohacking, intellectual property, and social justice. It is more or less the same checklist, which came from the programs dedicated to ELSI in nanotechnology.The mission of ELSI researchers is primarily to identify and clearly articulate a number of major issues raised by the development and diffusion of the emerging technology. And just as for nanoparticles, the discussions about the risks associated with synthetic biology center on the question: to what extent is it different from other biotechnologies? The risk issue inevitably shifts toward the question of novelty, which prompts two kinds of attitudes: the promoters of the emerging discipline are fond of revolutionary claims while people working for industrial companies rather emphasize continuity in order to reassure the public. On the one hand, Drew Endy and Rob Carlson claim the radical novelty of synthetic biology as they describe the current state of bioengineering as a modest bricolage. This unreliable tinkering with genes will be overcome by the more professional practices of the 1 In his lectures at Stanford University, the French philosopher Jean-Pierre Dupuy occasionally compares the confusion between ethics and prudence to the mistake of a physics student who would not make the distinction between weight and mass. Biobricks program based on the solid foundations of standardization, decoupling, abstraction 2 . On the other hand, when it comes to regulating industrial production, the Biotechnology Industry Organization (BIO) in Washington DC clearly states that there is nothing new or special about synthetic biology: "In our view, synthetic biology is an extension of the continuum of genetic science that has been used safely for more than 40 years by the biotechnology industry in development of commercial products" (Eickson et al. 2011). The kind of ethical research encouraged by synthetic biologists consists of prospective exercises meant to anticipate potential adverse effects. Ethics is focused on the identification of risks, and those risks are immediately balanced with the huge potential of benefits expected from the future applications of synthetic biology. Anticipating risks and making efforts to prevent them is considered as the ultimate responsible attitude. It means that the kind of ethics required by the proponents of synthetic biology has little in common with professional ethics. It is closer to the professional obligations of managers, including risk assessment, prospective studies and measures of prevention. Anticipating and preventing adverse effects is a managerial attitude. Synthetic biologists should go ahead and include upstream technical solutions to prevent potential risks. For preventing the dissemination of synthetic organisms and the risks of contamination of natural life, synthetic biologists demonstrate their prudence in suggesting novel forms of containment: in addition to the conventional measures of containment in laboratories, they plan to design synthetic microorganisms

Scientific and Technological Choices (OPECST) published a report in 2012 assessing the main ethical, economic, and social challenges of synthetic biology[START_REF] Fioraso | Les enjeux de la biologie de synthèse[END_REF]. However, no concrete initiative came to match the national ambitions[START_REF] Meyer | Aiming high, but investing little[END_REF], apart from the creation of an observatory of synthetic biology, which is in charge of a bioforum, a series of stakeholders debates to be held in 2013-2014.Science policy makers are obviously concerned although they are not presenting a wide range of proactive initiatives. The European Union launched a two-year project,Synbiosafe (2006Synbiosafe ( -2008)), which did

This underlying valuation has been the target of an artist's criticism through an extreme-art project. The exhibit Synth-Ethic in Vienna displayed "le cheval en moi" by Marion Laval-Jeautet who has been injected with horse immunoglobin for several months and gradually developed tolerance to the point of accepting a transfusion of horse blood. She claims that animal is the future of humans.