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3 How Do Macroscopic Functions of Life Emerge from Interactions Among Many Microscopic Constituents?
Pages 119-157

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From page 119...
... For a single cell, this behavioral scale is on the order of microns, something visible only through a microscope but still a thousand times larger than the nanometer scale of individual molecules. A major thrust of biological physics is to understand how to bridge these scales, from microscopic to macroscopic.
From page 120...
... First, what are the structures of these complex molecules? Second, what is the nature of the mapping between amino acid sequences and protein structures?
From page 121...
... Collective 152 Understanding the beautiful, New universality classes; Active matter; behavior coordinated movements direct inference of coordination of birds in a flock, insects statistical physics models of autonomous in a swarm; emergence of from data; non-classical vehicles. "construction projects" in modes of ordering.
From page 122...
... It would take decades until the first protein structures were revealed through the analysis of X-ray diffraction patterns, in the late 1950s and 1960s. These struc tures were not so precise as to reveal the positions of individual atoms, but showed clearly that the polymer of amino acids folded into local or "secondary" structural elements, helices and sheets, as had been predicted theoretically; these elements then pack into the overall globular structure of the protein.
From page 123...
... Adachi et al. Most recently, electron microscopy has taken its place alongside X-ray dif fraction and NMR as a method for protein structure determination.
From page 124...
... Some measure of the impact of these develop ments is in the stream of Nobel Prizes recognizing many of the breakthroughs: the first structures of proteins and other complex biological molecules (1962, 1964) ; the use of electron microscopy to solve structures with repeating units, as with the many proteins in certain viruses (1982)
From page 125...
... do not. Protein structures pack the hydrophobic amino acids into the core, leaving a shell of hydrophilic amino acids to interact with the surrounding water.
From page 126...
... Also indicated on the surface are highly FIGURE 3.3 If proteins are to be functional, only a tiny fraction of amino acid sequences aretrajectories simplified allowed. for the folding of Schematic energy landscape for protein folding, showing how the ensemble of unfolded structures is individual molecules.
From page 127...
... Statistical Mechanics in Sequence Space Although the typical random sequence does not fold, neither does every single amino acid along the polymer chain need to be chosen correctly in order for the protein to fold into a particular structure. Looking across the tree of life, and sometimes even within a single organism, there are many proteins with related but not identical sequences, and the different proteins in these families fold into very similar structures.
From page 128...
... Perspective Proteins represent a different organizational state of matter than is found in the non-living world, selected by evolution for particular functions but also for the more general task of folding efficiently into compact structures. The great expan sion of experimental methods for determining protein structures, now largely ex ported from biological physics into the structural biology community, encourages us to think more globally about the mapping between sequence and structure.
From page 129...
... New methods combining chemical labels with electron microscopy, as in Figure 3.4, hold promise, but there still is no full picture connecting the nanometer scale of the nucleosome to micron scale of the nucleus.
From page 130...
... space of the mammalian cell nucleus are visualized 5- to methods The list ofthat author affiliations is availa combine upon excitation, catalyzes chemical24-nm-diameter the depo- labeling and electron microscopy. granular chain that isLarge packed3Dtogether samplingatvolumes (rear block)
From page 131...
... The chromosome is a dynamic structure, and the experiments on single cells capture snapshots of these dynamics. Some sense for the frontier of this exploration comes from the fact that both the optical methods of Figure 3.5 and the chemical/genomic methods currently are limited to locating segments of the chromosome that are tens of thousands of base pairs in length.
From page 132...
... . Ideas from statistical physics have been used to identify the origin of these dynamics and to demonstrate that the robust scaling laws observed for chromosomal motion in vivo can arise from physical principles rather than system-specific biological mechanisms.
From page 133...
... Garini, 2009, Transient anomalous diffusion of telomeres in the nucleus of mammalian cells, Physical Review Letters 103:018102, copyright 2009 by the American Physical Society.
From page 134...
... It had long been known that purified versions of biological materials had interesting phases and transitions, but except in special cases -- such as the behavior of proteins in the lens of the eye -- it was never clear that this physics was relevant to the business of life. Over the course of a decade, this has changed dramatically, with novel phases, phase transitions, and phase separation becoming central to discussions of myriad processes in living cells.
From page 135...
... Near criticality, there are fluctuat ing domains on long length scales, and the spatial and temporal statistics of these fluctuations are predicted theoretically, by general statistical physics principles, with no free parameters; these predictions have been confirmed in detailed experiments on these membrane systems. The surprise is that real biological membranes have lipid compositions close to the critical point.
From page 136...
... The observation of liquid-liquid phase separation in the two dimensions of a membrane prepares us for the possibility that something similar happens in three dimensions with proteins and nucleic acids in the cytoplasm. Phase Separation in the Cytoplasm Understanding the principles that drive the organization of biological molecules into function-specialized machines known as organelles has been largely undertaken by biologists, not physicists.
From page 137...
... However, although the components of the disordered non-membrane bounded organelles were identified, the disordered nature of their structure and difficulty in achieving in vitro reconstitution made it difficult for biologists to decipher the physical principles driving their highly ordered formation. It came as a surprise that structurally disordered, non-membrane-bounded or ganelles form by the process of liquid-liquid phase separation.
From page 138...
... a quantitative description of the relationship between valency, affinity, concentra tion, and phase separation, which was similar to transitions from small complexes to large, dynamic supramolecular polymers that had been described in non-living systems. Subsequent demonstrations that phase separation actually affects protein activity led to the notion that phase transitions may be used to spatially organize and biochemically regulate information throughout biology.
From page 139...
... Finally, there are new physics questions about phase separation in the fundamentally non-equilibrium environment of the living cell. CELLULAR MECHANICS AND ACTIVE MATTER Living cells move.
From page 140...
... Pioneering efforts to derive these sorts of hydrodynamic theories for "active matter" were motivated by flocks and swarms (Chapter 3) , but in the same way that fluid mechanics is the same for many differ ent kinds of molecules, the hydrodynamics of active matter should be the same for all constituents that have the same symmetry properties.
From page 141...
... Rao, and R.A. Simha, 2013, Hydrodynamics of soft active matter, Reviews of Modern Physics 85:1143, copyright 2013 by the American Physical Society.
From page 142...
... Recently, quantitative theories and related experiments based on active matter ideas have addressed questions such as the size and shape of mitotic spindles and the cortical flow leading to polarization of worm embryos. Connecting to the World The cytoskeletal networks of filaments and motors inside the cell are linked to the environment outside the cell through integrin protein assemblies (see Figure 3.12)
From page 143...
... Perspective Active matter provides a perspective on the emergence of structure and function from interactions among motile components. From this perspective, in looking at the cytoskeleton the "particles" are molecules, while in tissues the particles are cells, but the physical principles are the same.
From page 144...
... Important successes often have become part of the mainstream of neuroscience, but the effort to understand collective behavior in networks of neurons continues to occupy a significant part of the biological physics community, as experimentalists develop new instruments for quantitative exploration of network dynamics and theorists use neural networks as a source of new problems in statistical mechanics. Observing the Human Brain Humans have a special interest in the dynamics of their own brains.
From page 145...
... Although much has been learned about the brain by studying the responses of single neurons, there was a gap between these measurements and ideas about emergent and collective behavior in networks of neurons. Closing this gap requires monitoring the electrical activity of many individual neurons, simultaneously.
From page 146...
... During an action potential, the electric field across the cell membrane changes by ∼107 V/m. This large field is enough to generate large changes in the optical properties of molecules in the membrane, and there were efforts dating back to 1970 to use voltage-sensitive dye molecules that would dissolve in the membrane and literally make the electrical activity of neurons visible as a change in fluo rescence.
From page 147...
... (B) FIGURE 3.13 Genetically encoded fluorescent proteins allow us to monitor electrical activity in many neurons simultaneously, at high signal-to-noise ratio.
From page 148...
... The second, alterna tive simplification is to imagine that all synaptic connections are symmetrical, in which case the dynamics of the network are equivalent to motion on an energy landscape. In both cases, ideas from statistical physics play a key role in the analysis; more deeply, these model neural networks have been the source of new statistical mechanics problems.
From page 149...
... An important challenge in searching for collective behavior in networks of neurons, as in many other living systems, is the absence of the usual macroscopic, thermodynamic probes. Even in models that map to well-defined statistical physics problems, order parameters are complex combinations of activity across the network; available experimental manipulations do not couple naturally to these order parameters (as with applying a magnetic field to a ferromagnet)
From page 150...
... Nonetheless, there is general agreement that the biological physics community has played, and will continue to play, a crucial role in the development of imaging techniques for the acquisition of data and in the devel opment of analysis techniques for image processing and the elucidation of neural circuits. Extensive challenges concern the successful visualization and tracing of trillions of axons and their synaptic connections, key constituents of a complete connectome, as illustrated in Figure 3.14.
From page 151...
... Moon, yA.W. Wetzel, et al., 2017, Whole-brain serial-section electron microscopy in larval x c zebrafish, Nature x 545:345, copyright 2017.
From page 152...
... The hope for the coming decade is that there will be not only continued, parallel progress in theory and experiment, but new ideas about how to build bridges between the two. COLLECTIVE BEHAVIOR Collective behaviors in animal groups provide some of the most familiar ex amples of emergent phenomena in living systems.
From page 153...
... FIGURE 3.15 Collective behaviors in animal groups, such as the large construction projects of ter mite nests, provide examples of emergent phenomena in living systems. Three-dimensional structure, reconstructed via X-ray tomography of a Cubitermes nest, from a set collected in equatorial forest regions of the Central African Republic and Cameroon.
From page 154...
... But there is no generic expectation for scale invariance of correlations in speed fluctuations. Although swarms of midges exhibit no overall velocity ordering, they too show scale invariant fluctuations in velocity, and analysis of correlations in both space and time reveals dynamic scaling, with an exponent closer to ballistic propaga tion rather than diffusion of information through the swarm (see Figure 3.16)
From page 155...
... These also are social behaviors, but evidently this term covers a much wider range of possibilities. In some cases, the collective behavior is so compelling that what emerges is a "superorganism," as with social insects such as termites, ants, and social wasps.
From page 156...
... The biological physics community's understanding of flocks and swarms began with somewhat complicated agent-based models from the biological literature and went through phases of simplification and deeper theoretical analysis, followed by dramatic improvements in quantitative measurement that exposed new statistical physics problems. The understanding of social insects seems somewhere near the beginning of this process, and it is encouraging to see new experiments probing the collective behaviors of honeybees, ants, and others using modern physics-based ap proaches.
From page 157...
... In flocks and swarms, and with social insects, the search for theories proceeds in parallel with dramatic improvements in experimental observations, and there are opportunities for substantial leaps forward in the coming decade. The world of collective behaviors is much larger than described in this section, and it is possible that the deepest insights will come from taming an example that currently is only barely explored.


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