C. R. Acad. Sci. Paris, t. 2, Série IV, p. 799–801, 2001Biophysique/Biophysics(Physique statistique, thermodynamique/Statistical physics, thermodynamics)

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LA PHYSIQUE À L’ÉCHELLE DE LA CELLULE

PHYSICS AT THE SCALE OF THE CELL

Avant-propos / Foreword

Biology has reached a stage comparable to chemistry and material science at the end of last century.Mendeleev’s periodic table was well established, there were a few missing elements and one couldreasonably think that the most important advances would concern these elements. It was indeed partly truesince the discovery of radioactivity is in some sense part of that game. This was also a large underestimate ofthe research to come: for instance the vast majority of material science which has deeply changed industriesfrom aeronautics to cosmetics, utilizes fairly standard elements, already well known at that time. Solidstate physics, electronics, opto-electronics, do not use uranium or more recently discovered elements. Yet,discoveries as important as superconductivity, superfluidity, semi-conductivity, transistors and lasers haverevolutionalized our knowledge and every day life. The impressive progresses of genomics give us theequivalent of Mendeleev’s table for biology. A gene may be considered as equivalent to an element in thatit can interact with other genes to generate structures of higher complexity and functionality, just as atomsinteract to make molecules. The genomic library is orders of magnitudes more complex than Mendeleev’stable: it is impossible to predict what will come out of its study. May be a new field of research will emergein a way similar to the emergence of radioactivity at the turn of last century, may be not. Irrespective of thispossibility, it is certain that the equivalent of material science will exist: many phenomena governing cellbiology, developmental biology or tissue behaviour have to be first understood at a semi-macroscopic levelbefore being understood at the genetic one. Just as it is still impossible, to predict the properties of a givenmaterial from first principles, it will be very hard to understand cell behaviour based on the sole knowledgeof genetics. Collective phenomena which take place in the tens to thousands of nanometers scale play avery important role in the shaping of life. They need to be studied and understood.

This is what the current issue ofComptes Rendus de L’Académie des Sciences illustrates: the mechanismsat work in life sciences are in many ways similar to those found in condensed matter. Self organisation aswell as phase transitions and dynamical transitions are very important. Our past experience tells us thateven though a good knowledge of the molecular level may seem to be the prerequisite to understandingmacroscopic phenomena, it is usually not sufficient. Metallurgy, polymer science, the physics of colloids,actually the whole of condensed matter sciences tell us that intermediate scales (i.e. from tens of nanometersto microns) are just as important, and sometimes even much more! Cell biology deals exactly with thesescales. It is reasonable to think that the techniques and concepts developped to analyse condensed matterwill be useful in casting the problems of cell biology in a proper framework. One of the key conceptsis that of phase transition or of dynamical transition. Continuous symmetry breaking transitions havedrawn a considerable amount of attention in the physics community over the last fifty years, discontinuoustransitions a little less but they are clearly very important for the computer technology and display devices.To what extent are these concepts relevant to biology? Their usefulness has often been quoted but alsooften disputed: in general one has to adjust at least one parameter (e.g. temperature) to set a system at atransition point: biology needs to operate in a fairly robust way and this seems to be incompatible with thenotion of adjusting one or several parameters. This series of articles illustrates, among other things, hownature can use transitions of both types. Detection of faint signals may use continuous transitions, controland command discontinuous ones. As a consequence, the relation between phenotype and genotype is ingeneral not simple: the change of the expression level (or degradation level) of a given protein causes thecellular system to cross a transition boundary and a new phenotype is observed. However, a given boundarymay be crossed by the change in several effectors: if we do not make the effort of patiently constructingthe dynamical state diagrams no matter how complex they can be, it will be very difficult to understand

S1296-2147(01)01224-0/EDI 2001 Académie des sciences/Éditions scientifiques et médicales Elsevier SAS. Tous droits réservés 799

J. Prost PHYSICS AT THE SCALE OF THE CELL

correctly cell biology. This remark does not invalidate all the efforts in genomics, it adds up an unavoïdablelevel of complexity.

Knowing that in a cell, there are about ten thousand different proteins, a thousand phospholipids, sugars,not to speek of nucleic acids, ions, etc., it seems totally hopeless to try to construct such diagrams. This isnot so because many important problems may be understood by a generic approach, which needs only retaina few crucial features. Much of superconductivity has been understood well before any microscopic theorywas constructed. It was only necessary to recognize that superconducting systems could be described by asingle wave function. Similarly nerve influx has been successfully described using a fairly reduced numberof ion concentrations, channels and pumps, and electric potential. This generic approach can nowerdays bepushed further in a very useful way. It does not preclude us from paying much attention to the specificityof proteins: it simply allows us to cast the problems in their proper frameworks.

Cells are characterized by their ability to self-organize and to perform functions: in this special issueof the Comptes Rendus de l’Académie des Sciences, adhesion, signal transduction, transport, adaptationand self-organization are discussed on specific examples. The first contribution deals with adhesion, whichis crucial for tissue differentiation, stability, signaling, etc. One of the most important messages is that theunderstanding of the physics of membrane adherence to substrates, requires the recognition of the existenceof a first order transition between a strongly bound and a weakly bound state: all experiments show phaseseparation phenomena with adhesive an non adhesive regions. This is due to the competition between therepulsion of the glycocalix and the adhesion of proteins. It provides a natural explanation for focal domainsand focal lines well characterized in cell biology. The second contribution constructs a physics adapted tomembranes driven out of equilibrium by active biological processes: much is known about the behavior ofmembranes close to equilibrium, but little is known when they are far from it. In particular their fluctuationsbecome significantly different from thermal fluctuations and new morphogenetic dynamical instabilitiesmay be predicted. Their biological relevance has to be carefully tested in the future.

A very important component of Eukaryotic systems is linear molecular motors. They are proteins able toride on polar cytoskeletal filaments when fuel is provided to them in the form of ATP (adenine triphosphate).The energy comes from the hydrolysis process ATP→ ADP (adenine diphosphate). The molecular aspectsof the mechanism providing the motion are very interesting and they will be discussed in a forthcomingissue of theComptes Rendus. What is discussed in the third contribution is their ability to generateself-organization in the many body motor/cytoskeleton system. Starting from a homogeneous, isotropicdistribution of both motors and cytoskeletal filaments (and fuel!) one spontaneously obtains symmetrybreaking patterns which mimic the mitotic spindle. In our physics jargon we would say that disclinationsare spontaneously generated. This type of experiments shows that it is possible to extract a few componentsof biological systems and study carefully their properties. This is clearly a way to go and much has to bedone along these lines: one can both address questions concerning the generic aspects of the problem athand, and specific questions concerning the role of proteins and protein mutations. The forth contributiondiscusses different aspects of mechanical oscillations in biological systems. They also involve motors andcytoskeletal filaments, but in a geometry very different from the one discussed in the preceeding paper: thatof muscles and axonemes. It is amazing how ubiquitous elements such as flagellae or axonemes can be!This illustrates one of the aspects of evolution: when a mechanism is ‘discovered’ by living systems there isa natural tendency to use it in a vast class of situations: this is a sort of universality very different from theone we know in physics. This does not mean that the universality we know, for instance close to continuoustransitions, does not play a role: the very surprising properties of hearing may be traced down to the activityof hair cells close to a continuous Hopf bifurcation, in the presence of fluctuations!

The fifth article describes a beautiful system which in some ways resemble Maxwell’s demon: the nuclearpore. Normal cell life requires that some molecules like packing or transcription proteins swimm across itfrom the cytoplasm to the nucleus, others like messenger RNA in the opposit sens. How is it possible toachieve such a complex function with only a few errors? The review shows that enough is known today tostart a physics approach.

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PHYSICS AT THE SCALE OF THE CELL Avan-propos / Foreword

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The above contributions describe some of the phenomena underlying cell activity and it is clear thatin order to obtain a unified picture, one will have to consider all these elements simultaneously. Yet animportant element will be absent: the chemical control of the processes (not to speak of the genetic control).The last contribution shows on a clever model how robust amplification of a signal can be achieved by analmost perfectly adaptative transduction network. Indeed, many biological systems such as bacteria canlive under extremely different conditions. As a result any amplification process must be able to work ina very wide range of external parameters and simultaneously maintain a high gain. The system cannot befine-tuned and must exhibit robustness: the inhibition-driven amplification proposed in this last contributionachieves this goal in a natural way.

This issue contains a few examples of biological problems in a field which is growing very fast. Thenumber of questions which seem addressable by physics is amazingly large. Typical goals, would be forinstance to understand in a generic way (i.e. establish the relevant dynamical state diagrams) all importantcell functions, and ultimately how pluripotent stem cells can differentiate specifically. The main impactwould probably be on medicine since one should then be able to ‘play’ with cell behavior in a very mildand subtle way. On a more egoïstic side, this field of research is interesting on a physics point of view sinceit deals with problems in which the fluctuation dissipation theorem is not obeyed, which allows for a largenumber of new situations with non trivial and often counterintuitive behaviors.

Jacques ProstUMR 168 CNRS/IC, Institut Curie, section de recherche,

26, rue d’Ulm, 75248 Paris cedex 05,France

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