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W4241743907 abstract "In the early nineteenth century, views on the nature of living organisms were broadly divided into two categories, chemical and vitalist. The former held that life was a consequence of complex, but ultimately knowable physicochemical processes, while the latter posited some nonnatural, perhaps unknowable, properties of living systems. Vitalism was progressively undermined by Wohler's synthesis of urea (1828) and by Pasteur's inability to demonstrate spontaneous generation (1862), as well as by Darwin's Origin of Species (1859) and Virchow's cell theory (1855). By the turn of the twentieth century the remarkable properties of living systems were more evident than ever, but vitalism was no longer invoked to explain them. The modern scientific quest for the chemical basis of life had begun in earnest. Although heredity was known as an important property of living organisms, investigations of the chemical basis of life concentrated as much on other attributes, such as metabolism and movement. At the close of the twentieth century, genetics reigns triumphant as the central theme in biological thought. The sequence of the human genome is widely seen as the starting point for biological investigation in the next century, and the debate on the origin of life largely defines “alive” as equivalent to “accurately transmitting a genetic blueprint.” We do not question the importance of genetics, nor dispute the role of DNA as the blueprint for all the components of living systems, but we think it worth asking to what extent the “postgenomic” view of modern biology would convince a nineteenth century vitalist that the nature of life was now understood. How close are we to understanding how a single cell functions or how an embryo develops? If the answer is not so close, will true understanding of living systems come from further annotating the database of genes, or must we explore the physicochemical nature of living systems? In this essay we discuss a few personal favorite examples, starting from macromolecular assembly and increasing in complexity and scale to patterning in vertebrate embryology. Our discussion illustrates the nature of biological organization and explores the potential chemical principles behind them. Although the units we consider, proteins, cells, and embryos are manifestly the products of genes, the mechanisms that promote their function are often far removed from sequence information. In a light-hearted, millennial vein we might call research into this kind of integrated cell and organismal physiology “molecular vitalism.” Analogies to machines are widely used in molecular biology to understand the nature of cellular processes. The DNA replication apparatus, spliceosome, nuclear pore, and ribosome all have substructures, moving parts, and integrated assemblies like conventional machines (Cell, 1998). Yet other biological systems, which might seem machine-like, on closer examination operate on very different principles. Even the simple signal-response of an allosteric enzyme is not machine-like when examined in detail. Allosteric proteins have intrinsically active and inactive conformations, which exist in some ratio in the absence of an external signal (23Monod J Wyman J et al.On the nature of allosteric transitions a plausible model.J. Mol. Biol. 1965; 12: 88Crossref PubMed Scopus (6130) Google Scholar, 16Henry E.R Jones C.M Hofrichter J Eaton W.A Can a two-state MWC allosteric model explain hemoglobin kinetics?.Biochemistry. 1997; 36: 6511-6528Crossref PubMed Scopus (97) Google Scholar). Interconversion between the states is spontaneous, driven by thermal energy. Allosteric effectors bind preferentially to one of the states, perturbing the equilibrium, and leading to inhibition or activation. However, the allosteric effector does not directly change the chemistry or conformation of the protein appreciably, but merely stabilizes one of the two preexisting states—a case of state selection. Like macroscopic machines there is an input and an output, but unlike machines the intervening linkages are statistical and not mechanical. More complex “protein machines” like the ribosome can bias the statistics toward determined outcomes by hydrolyzing NTP, but the essential role of statistical thermodynamics in their levers and springs should not be forgotten. Bacterial chemotaxis also appears superficially to be a simple signal-response machine, where an attractant or repellent is perceived by receptors on the bacterial surface to generate a signal that is converted to directed movement. We could imagine all sorts of linkages that would control a motor or a steering mechanism to guide the bacterium by chemical signals. In fact, bacterial chemotaxis is based on the modulation of random movement by ligand binding, resulting in a biased random walk. The specific path any bacterium takes is not directly informed by the binding of the ligand, nor does the individual bacterium at any moment sense a spatial gradient (3Berg H A physicist looks at bacterial chemotaxis.Cold Spring Harbor Symp. Quant. Biol. 1988; 53: 1-9Crossref PubMed Google Scholar). This is quite different from any machine of human design! Biological systems look even less like machines when one considers spatial organization. They can generate order from disorder and can arrive at functional states and responses over a range of starting points, sizes of components, and sizes of final product. As an example, consider the relationship between cell size and the size of the organism. In the 1940s Gerhard Fankhauser experimented with the effects of ploidy on newt development (9Fankhauser G Maintenance of normal structure in heteroploid salamander larvae, through compensation of changes in cell size by adustment in cell number and cell shape.J. Exp. Zool. 1945; 100: 445-455Crossref PubMed Scopus (84) Google Scholar). Polyploid embryos, generated by suppressing early cleavages, had fewer but larger cells. Cells in all tissues were affected, but the tissues of the organism and the adult itself remained the normal size. The consequence of ploidy was seen most clearly in well-defined structures, such the pronephric duct (the earliest kidney rudiment). Fankhauser found that the average number of epithelial cells forming the duct decreased with increased ploidy, while the duct size and wall thickness remained the same diameter! As shown in Figure 1, in pentaploid embryos there were just one to three cells straining to maintain a circular duct of dimensions that required three to five cells in diploid embryos and five to eight cells in haploid embryos. In 1945 Albert Einstein wrote Fankhauser, “Most peculiar, however, for me is the fact that in spite of the enlarged single cell the size of the animal is not correspondingly increased. It looks as if the importance of the cell as ruling element of the whole had been overestimated previously. What the real determinant of form and organization is seems quite obscure” (10Fankhauser G Memories of great embryologists.Amer. Scientist. 1972; 60: 46-55PubMed Google Scholar). Today we might not draw such a strong conclusion about the role of the cell, but we might be tempted to ask what cell biological properties can we draw upon to explain “the real determinant of form and organization”? What was the driving force for pronephric duct size that could operate despite changes in cell size? The basis of our understanding of supramolecular structure has been the doctrine of self-assembly. Self-assembly is an extension of the central dogma of molecular biology, bringing us from the realm of linear information to the realm of protein assemblies (5Caspar D.L.D Klug A Physical principles in the construction of regular viruses.Cold Spring Harbor Symp. Quant. Biol. 1962; 27: 1-24Crossref PubMed Scopus (1876) Google Scholar, 25Oosawa F Asakura S Thermodynamics of the Polymerization of Protein. Academic Press, London1975Google Scholar, 18Inoue S The role of self-assembly in the generation of biological form.in: Subtelny S Green P.B Developmental Order Its Origin and Regulation. A.R. Liss, New York1982Google Scholar). It is exemplified by a virus particle, which generates a single highly ordered (to atomic dimensions) structure that is “uniquely determined by size, number of components, geometry, and strength of interaction” (14Gerhart J Kirschner M Cells, Embryos, and Evolution. Blackwell Science, Boston, MA1997Google Scholar). Typically systems of self-assembly reach equilibrium, a state of minimum free energy. Today a postgenomic view of self-assembly would extend this concept to a description of how each gene product functionally interacts with other gene products. These pair-wise interactions can be used to describe protein complexes and pathways of interaction. They could form the basis of our future understanding of higher level organization and information transfer in biological systems (13Frederickson R Macromolecular matchmaking advances in two-hybrid and related technologies.Curr. Opin. Biotechnol. 1998; 9: 90-96Crossref PubMed Scopus (34) Google Scholar). Self-organization is an extension of self-assembly, but employing several new chemical principles (21Kirschner M Mitchison T Beyond self-assembly from microtubules to morphogenesis.Cell. 1986; 45: 329-342Abstract Full Text PDF PubMed Scopus (978) Google Scholar). In contrast to self-assembly, self-organization gives “structures under a wider set of condition; the rules tend to be more general and the structures more variable” (14Gerhart J Kirschner M Cells, Embryos, and Evolution. Blackwell Science, Boston, MA1997Google Scholar). Self-organizing systems are characterized by reaching a steady state, where there is continuous energy consumption and gain and loss of material. In discussing examples of self-organization, we will focus on two of the most archetypal and unusual biological properties: (1) the capacity for unitary organization, also called polarization; and (2) the capacity to generate nearly regular biological structure when size and composition of components are altered, also called regulation. These properties are not what we would expect from mechanical processes, and no machines of human design evince such properties. They are a manifestation of complex yet robust chemical processes, some of which we are beginning to understand, some of which seem as remote as Fankauser's ploidy experiments. In many biological systems the first step in generating spatial complexity is the breakdown of a symmetrical structure into a more organized asymmetric or polarized structure. 33van Oudenaarden A Theriot J Cooperative symmetry-breaking by actin filament polymerization in a model for cell motility.Nat. Cell Biol. 1999; 1: 493-499Crossref PubMed Scopus (120) Google Scholar recently described a simple model of this process in the generation of polarized arrays of actin; their explanation for spontaneous symmetry breaking in this system provides new clues to principles of self-organization. Listeria monocytogenes, an intracellular pathogenic bacterium, hijacks the natural actin nucleation machinery of the cell and propels itself through the cytoplasm by triggering assembly of a polarized “comet tail” of actin. A single secreted protein of the bacterium, Act A, is sufficient to induce actin assembly. In their experiments Act A was purified and adsorbed uniformly on the surface of spherical polystyrene beads. When the beads were placed into a cellular extract, actin was initially polymerized in a symmetrical manner. With time actin assembly became asymmetric and the bead ultimately generated a single, completely polarized comet tail that propelled it through the extract (Figure 2). Several questions arise. How is a symmetrical condition transformed into an asymmetric one? How do the individual actin filaments around the bead “communicate” to each other, so that actin is only significantly polymerized in one region and not another? Why is there always a single tail produced? van Oudenaarden and Theriot postulate that actin polymerizing against the bead exerts a force and the bead is continually buffeted by the actin pushing against the viscous nature of the surrounding fluid and the surrounding crosslinked actin filaments. Stochastic differences move the bead and these stochastic differences are amplified by the biophysical properties of actin assembly. As the bead moves, actin filaments on one side are inhibited in their polymerization, while actin filaments on the pushing side polymerize more readily. Symmetry once broken is exaggerated and the system becomes stable with a single tail. This simple biophysical model achieves characteristics that, had they been observed in a cellular setting, might have been ascribed to external influences and complex regulation or at least to intrinsic asymmetry of the nucleating structure. Despite the absence of external forces or preorganization to break symmetry, a single polarized array self-organizes. It appears that amplification of a random inequality through mechanochemical coupling provided by the nondeformable bead is sufficient to generate spontaneous polarization. We see in this example that self-organization of an array of actin filaments is built on the self-assembly of individual filaments. In a dynamic system a variety of configurations of these filaments can be generated from stochastic differences at the molecular level. To achieve a unitary structure, albeit oriented at random, requires rapid off-rates and some large-scale force or structure that can serve to link the behaviors of the individual polymers. Actin assembly is made more dynamic by hydrolysis of ATP in the actin subunit. The formation of a single tail is an inevitable consequence of the kinetics of assembly, the response of assembly to compressive forces, and the existence of simple boundary conditions. Thus, self-organization can have a rather simple chemical and physical explanation. In the Listeria system a weak initial bias is sufficient to entrain the polarized array in a specific direction. This conclusion could hold at a cellular level as well. In an example that might be mechanistically similar to Listeria, Borisy and coworkers showed that radially symmetrical fragments of motile cells could be induced to polarize and initiate persistent unidirectional locomotion by subjecting them to a weak external force from a jet of fluid (34Verkhovsky A.B Svitkina T.M Borisy G.G Self-polarization and directional motility of cytoplasm.Curr. Biol. 1999; 9: 11-20Abstract Full Text Full Text PDF PubMed Scopus (391) Google Scholar). A more complex example is polarization of budding yeast. In this system the initial cue is usually provided by chemical “landmarks” in the cell wall or a gradient of mating pheromone, but in the absence of these cues the yeast cell will spontaneously self-polarize on a random axis (7Drubin D Nelson W Origins of cell polarity.Cell. 1996; 84: 335-344Abstract Full Text Full Text PDF PubMed Scopus (900) Google Scholar). The mitotic spindle provides a more complex system in which to explore principles underlying the spontaneous self-organization of collections of proteins in the cytoplasm. The spindle is an ordered array of microtubules, motors, and chromosomes that assembles at the beginning of mitosis. Once all the chromosomes are attached and aligned, the spindle reaches a steady state, termed metaphase. The time-invariant average structure of the spindle at metaphase might suggest it had attained thermodynamic equilibrium like an assembled virus, but dynamic imaging quickly dispels this notion. In fact the chromosomes constantly move back and forth around their average position, and microtubules polymerize continually at certain locations while depolymerizing at others, generating rapid turnover of individual microtubules and directed movement of the microtubule lattice. These dynamics require continuous energy dissipation, notably from GTP hydrolysis coupled to tubulin polymerization and ATP hydrolysis coupled to force generation by molecular motors. Steady-state thermodynamics can help us understand some of the implications of continuous energy dissipation by a self-organizing system like the spindle. The steady state resembles equilibrium in the sense that the system moves spontaneously downhill over some energy landscape to reach the steady state, where it comes to rest. If a steady state is perturbed, it will return to its preferred parameters. For example, if the length or organization of a spindle is perturbed by physical changes, drugs, or micromanipulation, and the perturbing agent is then removed, the spindle returns to normal over a few minutes (19Inoue S Sato H Cell motility by labile association of molecules. The nature of mitotic spindle fibers and their role in chromosome movement.J. Gen. Physiol. (Suppl.). 1967; 50: 259-292Crossref PubMed Scopus (499) Google Scholar). This robustness provides error-correcting mechanisms that are thought to be important to ensure accurate chromosome segregation (24Nicklas R.B How cells get the right chromosomes.Science. 1997; 275: 632-637Crossref PubMed Scopus (510) Google Scholar). Figure 3 shows an example of a spindle responding to, and recovering from, high pressure that depolymerizes microtubules. Prigogine, building on the work of Onsager, proved that a system comes to steady state when the rate of free energy dissipation is minimized, at least for a system not too far from thermodynamic equilibrium (26Prigogine I Introduction to the Thermodynamics of Irreversible Processes. Thomas, Springfield, IL1955Google Scholar). The concept of the steady state as a thermodynamic minimum helps us understand the ultimate driving force behind self-organization, and may account in energetic terms for much of the robustness and pathway-independence of a process like spindle assembly. Two types of protein–protein interactions are thought to drive spindle assembly: tubulin–tubulin interactions and tubulin–motor protein interactions. Assembly driven by motors means that initially random microtubules can slide actively past each other to achieve correct positions. Such motor driven sorting is thought to be a major force in spindle assembly (35Walczak C Vernos I Mitchison T.J Karsenti E Heald R A model for the proposed roles of different microtubule-based motor proteins in establishing spindle biplority.Curr. Biol. 1998; 8: 903-913Abstract Full Text Full Text PDF PubMed Scopus (328) Google Scholar). Tubulin–tubulin interactions in the microtubule lattice are coupled to GTP hydrolysis, which powers rapid microtubule turnover by drastically increasing the off-rate (21Kirschner M Mitchison T Beyond self-assembly from microtubules to morphogenesis.Cell. 1986; 45: 329-342Abstract Full Text PDF PubMed Scopus (978) Google Scholar). This process, termed dynamic instability, accelerates the rate at which microtubules probe cellular space (17Holy T.E Leibler S Dynamic instability of microtubules as an efficient way to search in space.Proc. Natl. Acad. Sci. USA. 1994; 91: 5682-5685Crossref PubMed Scopus (179) Google Scholar), and destabilizes incorrect organizations relative to the correct ones (21Kirschner M Mitchison T Beyond self-assembly from microtubules to morphogenesis.Cell. 1986; 45: 329-342Abstract Full Text PDF PubMed Scopus (978) Google Scholar). Motor-dependent assembly interactions and dynamic instability collaborate to make incorrect or partial assemblies dissipate energy faster than the correct one, and together provide a thermodynamic drive to the assembly of functionally correct structures. This picture of self-organization to a thermodynamic minimum at steady state is likely applicable to many, perhaps all, cellular assemblies. Its relevance to other cytoskeletal arrays like the actin-based leading edge of migrating cells is obvious. Less obvious and perhaps more interesting is the relevance of steady-state thinking to dynamic membrane systems such as the Golgi apparatus. Like the spindle, the Golgi apparatus is an inherently steady-state structure in which continuous fluxes of material and energy are inherent to spatial organization. Proteins that use NTP hydrolysis to drive conformational cycles, such as arfs, rabs, NSFs, and dynamins, play central roles in Golgi organization (27Rothman J.E Wieland F.T Protein sorting by transport vesicles.Science. 1996; 272: 227-234Crossref PubMed Scopus (1023) Google Scholar). Energy dissipating fluxes through biochemical cycles of lipid modification may also play a central role in self-organization of membrane systems (29Schmidt A Wolde M Thiele C Fest W Kratzin H Podtelejnikov A.V Witke W Huttner W.B Soling H.D Endophilin I mediates synaptic vesicle formation by transfer of arachidonate to lysophosphatidic acid.Nature. 1999; 401: 133-141Crossref PubMed Scopus (449) Google Scholar). So far we have discussed examples of self-organization within a single cell that are not very far removed from self-assembly. How complex can self-organization be in a single cell? About a billion years ago, after the basic attributes of eukaryotes had emerged, one branch of the eukarya invented multicellularity and became the metazoa. But the unicellular organisms did not stop evolving, and today we can see among them examples of remarkably complex spatial organization. Unicellular organisms often assemble the equivalent of multiple different, specialized organs arranged in a specific body plan. Developmental phenomena resembling spatial gradients and induction have been observed in such organisms. Impressive examples of size-independent patterning and recovery from drastic perturbation attest to robust, self-organizing mechanisms for spatial patterning. To bridge between protein assemblies and metazoan embyronic developmental systems, we will consider what is known of self-organization mechanisms in a large ciliate, Stentor coerulus. Stentor is a very large (up to 1 mm), trumpet-shaped, ciliated protozoan that lives in water with its pointed end (foot) typically attached to a substrate. It feeds by sweeping smaller organisms into a gullet through the action of rows of fused cilia in the oral apparatus at its broad end. Much of our knowledge of Stentor derives from the devotion of one man, Vance Tartar, who worked on them from 1950 to 1978 in an 8' × 10' shed named “Wits End” at the bottom of his garden on the Washington coast, and published a large monograph on their biology (32Tartar V The Biology of Stentor. Pergamon Press, Elmsford, NY1961Crossref Google Scholar; see also 12Frankel J Whiteley A.H Vance Tartar a unique biologist.J. Eukaryotic Microbiol. 1993; 40: 1-9Crossref PubMed Scopus (5) Google Scholar). Tartar was fascinated by the ability of Stentor to recover from surgical operations, which allowed him to test theories of how the spatial pattern of the organism developed. Conceptually these experiments resembled classic manipulations of multicellular embryos that led to such discoveries as Spemann's organizer, but they involved removing, rearranging, or transplanting pieces of a single cell (Figure 4). How it is possible for a single cell to survive being cut into fragments is a fascinating question in its own right. Typical of ciliates, most of the spatially organized structures in Stentor are associated with a microtubule-rich cortex dominated by parallel rows of regularly spaced basal bodies running along the principle axis of the organism. Between these rows are pigmented stripes. The basal bodies are connected together within and between the rows by bundles of microtubules and other fibers in a quasi-regular geometric arrangement. The body plan of all ciliates is dominated by this structured cortex, giving the sense that their self-organization can be thought of as a problem in geometrical patterning of a two-dimensional sheet. Stentor's body plan involves two developmental axes. An apical-basal (A-B) axis is defined by the basal foot and the apical oral apparatus. A circumferential axis is evident from the spiral geometry of the oral apparatus. It is also evident from, and perhaps defined by, a circumferential gradient in the width of the stripes. This continuous gradient generates a unique line where the widest and narrowest stripes abut, called the locus of stripe contrast (LSC). Surgical manipulations revealed that the body plan of Stentor self-organizes by robust pathway- and size-independent mechanisms (Figure 4). Tiny cell fragments made by surgery can recover to form normally organized Stentor as small as 0.1% of the normal volume. These mini-Stentor gradually enlarge as they feed. Several conclusions emerged from surgical manipulations: To survive and recover, a Stentor fragment must contain some of the old cortex. A nucleus is also required for prolonged survival. Certain abnormal body plans produced by surgery, such as side-by-side conjoint twins, do not recover, but rather propagate as stable clones. During reestablishment of patterning after surgery, both the A-B and circumferential axes act as if they contain gradients of developmental potential. The LSC induces nearby cortex to assemble the new oral apparatus following normal cell division or surgery. This action of the LSC on nearby cortex formally resembles embryonic induction, a process whereby a group of cells (as opposed to a region of cytoplasm in Stentor) signals a responding cell population to generate the major structures of the vertebrate axial body plan. Interestingly, in Stentor an LSC active in signaling the adjacent cytoplasm can be formed surgically anywhere on the cortex at any point where broadly and narrowly spaced stripes are made to abut. We know very little about how Stentor, or any other ciliate, self-organizes a specific body plan. How can we begin to think about such mechanisms? Extensive recovery of anucleate fragments implicates largely posttranscriptional mechanisms. The requirement for some cortex for recovery from surgery, and the stability of conjoint twins, might reflect mechanisms of basal body replication and insertion. New basal bodies form in association with old ones, and the position and geometry by which a new basal body is inserted into a row is governed by the old ones in the row (2Beisson J Sonneborn T.M Cytoplasmic inheritance of the organization of the cell cotrtex in Paramecium aurelia.Proc. Natl. Acad. Sci. USA. 1965; 53: 275-282Crossref PubMed Scopus (265) Google Scholar). We do not know the exact mechanisms here, but some kind of structural templating seems to be operating (1Aufderheide K.J Rotolo T.C Grimes G.W Analyses of inverted ciliary rows in Paramecium. Combined light and electron microscopic observations.Eur. J. Protistol. 1999; 35: 81-91Crossref Scopus (8) Google Scholar). One could imagine a gradient of a diffusible factor specifying A-B position in Stentor, though there is no direct evidence for such a factor. How the circumferential axis in Stentor is generated, and how the LSC works, are completely mysterious. Any proposed mechanism for self-organization of Stentor, or other ciliates, will have to account for size regulation. Ciliate morphogenesis may now be accessible at a molecular level in Tetrahymena, which has a well-developed genetic system with mutants having interesting abnormalities in global patterning (11Frankel J Cell biology of Tetrahymena thermophila.Methods Cell Biol. 2000; 62: 27-125Crossref PubMed Google Scholar). Metazoan multicellular development, as it has evolved in the past billion years, is an accomplishment in the informational realm, that is, of organizing cellular processes spatially and temporally. Most organization is achieved in the steps of development before cell types differentiate and begin their physiological functions. Since the organization of the multicellular adult animal is so much more complex than that of the single-celled egg from which it develops, embryonic development has long been thought to consist of numerous self-organizing processes. How is this self-organization achieved? The old view that the egg's cytoplasm possesses the equivalent complexity of the adult, in an invisible molecular miniaturized form, is clearly incorrect. And anyway, this proposal just pushes back to an earlier stage the question of how organization is established. In embryonic axis formation, the initial organization of the embryo along anteroposterior and dorsoventral axes is established, much like the organization in Stentor, except in this case the organization is provisional and used in subsequent processes to build up greater complexity. A number of self-organizing processes operate at these early times. As expected for processes of initial organization, these, like the example of polarized actin growth off beads, have no or little dependence on prior organization. They can respond to such organization if it is present or can generate it stochastically, if not present. Since the initial symmetric arrangement of contents is lost when a new axis is formed, the process is a symmetry-breaking process. There are many kinds of symmetry breaking. Some occur in oogenesis (e.g., Drosophila), some at fertilization (amphibians, ascidians), and some at multicellular stages (molluscs, birds, mammals). Some use the cytoskeleton, (amphibians, ascidians) some use internal singularities such as the aster (amphibians, fish), and some use the packing of cells in small groups (mouse, nematodes). The common theme in all of these is an amplifying process that starts from a small random departure from perfect symmetry, building that into a major departure, which is the new axis. In most cases, the orientation of the new axis doesn't matter. What does matter is that there is one anterior–posterior axis (or one dorsal–ventral or left–right axis) and only one of each of these. Symmetry breaking is ex" @default.
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W4241743907 title "Molecular “Vitalism”" @default.
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