20 July 2012
This evidence mainly consisted in examples of unexpected plasticity, or adaptive capability, in whole-organism behavior.
In installment five, I began exploring an alternative view of life as an emergent phenomenon within an overall framework of physical emergence that has been developed by investigators in condensed-matter physics over the past half century.
Last time, I began the task of exploring specific ideas that have been proposed by various scientists as an alternative explanation of the intelligent agency and adaptive capability that constitute the essence of life.
In particular, I looked at UCLA physiologist F. Eugene Yates’s notion of homeodynamics. This theory, or heuristic, borrows concepts from nonlinear dynamics in order to provide a more adequate description of the actual behavior of living systems than that offered by traditional computational and cybernetic models and theories.
Nevertheless, homeodynamics also has its limitations. Notably, it does not by itself explain why the robust and plastic behavior it so well describes should exist in the first place.
That is, homeodynamics is a fairly high-level, or “phenomenolgical,” theory. As such, it needs to be connected up somehow with a deeper theory, if we are to achieve real insight into how life is possible.
In short, we still have a long way to go to answer the crucial question: “What might an organism be, if not a machine?”
With that end in view, in this installment I will discuss three empirically well-attested physical properties of living systems. Together, these three properties will strongly reinforce the conclusion that organisms are very different indeed from man-made machines.
More importantly, they will point us in the direction of a more fundamental source of insight into the nature of life—namely, the condensed-matter physics of the living state of matter.
But before exploring those implications—which I intend to do in future installments of this series—first let us review what is known about some of the most unusual and interesting physical properties of living systems.
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Too often, we envision the cell as a “factory” containing a fixed complement of “machinery” operating according to “instructions” (or “software” or “blueprints”) contained in the genome and spitting out the “gene products” (proteins) that sustain life.
Many things are wrong with this picture, but one of the problems that needs to be discussed more openly is the fact that in this “factory,” many if not most of the “machines” are themselves constantly turning over—being assembled when and where they are needed, and disassembled afterwards. The mitotic spindle (top) is one of the best-known examples, but there are many others.
Funny sort of “factory” that, with the “machinery” itself popping in and out of existence as needed!
No one has discussed the implications of the just-in-time self-organization of cellular structures with greater emphasis, eloquence, and profundity than Alexei Kurakin.
Kurakin is currently with the Department of Pathology at Beth Israel Deaconness Medical Center in Boston, as well as at Harvard Medical School. He has published a series of highly thought-provoking papers that ought to be much better known than they are.
Kurakin is remarkable, above all, for his sensitivity to the philosophical problems lurking within the mainstream interpretation of our exploding fund of empirical knowledge in biology.
For example, here is the way he frames the self-organization question:
Paradoxically, extraordinary advances in our understanding of the parts do not seem to bring about significant progress in our understanding of the whole. In fact, it appears that the design of the cell becomes increasngly elusive as experimental data accumulate. . . . Quantitative visualization of fluorescently tagged proteins inside living cells shows that most, perhaps all, sub-cellular structures and macromolecular complexes exist not as pre-assembled and relatively stable structures, but as highly dynamic steady-state macromolecular organizations, conceptually similar to a treadmilling actin filament but of greater complexity.(1)
. . . the mechanistic conceptualization of molecular motors often leads to “surprises” in experimental outcomes rather than provides a unifying interpretational framework of reasonable predictive power. Perhaps due to problems with self-consistency between different motor models, the current reviews on molecular motors give the impression of a chaotic mosaic of individual case micromodels, often of staggering complexity, where one would expect to see a self-consistent, systemic and structured description of the phenomenon.(2)
Defying the ideas of design and clockwork determinism, a leitmotiv of the latest experimental research are the uniquitous observations of self-organization and stochasticity that appears to emerge as general principles underlying the dynamics and organization of life at all scales. Stochastic molecular motors, stochastic enzymes, stochastic self-organization of cytoskeleton structures, sub-cellular and sub-nuclear compartments, stochastic self-organization of macromolecular complexes mediating transcription, DNA repair and chromatin structure/function, stochastic gene expression and stochastic cellular responses are poorly compatible with the familiar notions of design, programs, instructions and codes, and their systematic appearance is a call for active efforts to loosen the grip of the conventional mechanistic models and concepts in a search for an alternative and more adequate description of life systems.(3)
Another remarkable thing about Kurakin is his willingness to call a spade a spade. He seems to lack entirely the defensiveness one often encounters in the writings of biologists, too many of whom are singularly disinclined to admit what they don’t know:
. . . the newly revealed and unexpected properties—such as steady-state character, transient self-organization on demand, stochastic dynamics and interconnectedness—that characterize cellular structures and molecular machines believed to exist as pre-assembled complexes designed for certain functions according to programs and blueprints, clearly suggest the inadequacy of expectations and assumptions based on the mechanistic intuition.(4)
Kurakin does not have a master theory with which to replace the machine metaphor in biology. But he understands the elementary logical point that one does not need to have a better theory in order to know that a given theory—in this case, the standard Darwinian-mechanistic understanding of life—is unworkable.
Therefore, he contents himself with a precise and detailed description of the problem:
. . . it should be pointed out that, in reality, the internal resource distribution/transport systems of biological organisms (at all scales) are not mechanistic pipes built according to a preconceived design, but dynamic and adaptive fluxes of energy/matter in themselves, shaped by both internal and external influences. And their main purpose is not to deliver resources and remove waste—that is the limited interpretation of the mechanistic paradigm—but to integrate energy/matter and space into one scale-free continuum of energy/matter circulation.(5)
Of course, we must be clear that the “self-organization” discussed by Kurakin—and increasingly by many other biologists—is not in itself the solution to the riddle of life. Rather, it is a description of an aspect of the riddle.(6)
But admitting that there is a problem is a prerequisite to finding the solution. And little in contemporary biological discourse is more salutary for this purpose than the highly stimulating writings of Alexei Kurakin.
Another fundamental feature of life that is far too little acknowledged and discussed, though it is hardly a secret, is the fact that the primary agents of biological action—proteins (especially enzymes)—are highly dynamic entities.
The logic of Darwinian explanation depends upon representing proteins as deterministic, essentially static structures. In particular, enzymes are “keys” that have come to fit corresponding “locks” through a stochastic process at the genetic level that leads to aleatory results at the physiological (or “phenotypic”) level.
That is, according to Darwinian logic—and in keeping with the machine metaphor—genes have agency and enzymes are nothing more than mindless cogs in the cellular “machinery.” Proteins—on the mainstream interpretation—are just genes’ way of making more genes.
The truth, however, is more nearly the reverse. In itself, DNA is practically inert. Most of the functionality of the genetic material is expressed through the incessant intervention of other molecules, principally proteins.
DNA is a stable template by means of which some proteins generate other proteins, as required. Proteins, not genes, are the active agents in the cell. Therefore, it would be far closer to the truth to say that genes are proteins’ way of making more proteins.
Still closer to the truth, of course, would be to say that both proteins and genes are cells’ way of making more cells. But be that as it may, the question that arises from a right understanding of causality within the cell is this: How can proteins be “active agents”?
The answer is that the traditional picture of enzymes as relatively static “keys” floating around until they happen to bump into corresponding “locks” is radically flawed. We now know that the reality of protein dynamics differs from the classical mechanistic picture in several fundamental respects.
First, proteins are frustrated systems. “Frustration” is a technical term in physics meaning that a system in incapable of relaxing into a single lowest-energy state. The reason for this is a myriad of competing self-interactions among different parts of the system. As a result, the system as a whole incessantly and rapidly traverses a very large set of nearly isoenergetic, conformational substates.
In other words, proteins resemble not so much the traditional static structures depicted by X-ray diffraction (which are only averages), as essentially dynamic, writhing masses of fleeting configurations that have been described as “kicking and screaming.”(7)
Moreover, the collection of conformational substates visited by the system as a whole is itself hierarchically structured. Only some of the substates appear to be important for biological functioning. This observation has given rise to the concept of a subset of “functionally important motions” within the overall energy “landscape” of the protein.(8)
Most of these observations are not new, but technical means for effectively probing the energy landscapes of proteins are of more recent vintage. Analogical comparison between the properties of proteins and those of certain non-living systems—mainly glasses and supercooled liquids—has helped to throw light on the physical situation. However, no comprehensive theory explaining the relation between a protein’s energy landscape and its functionally important motions exists, as yet.
Nevertheless, it is safe to say that with the concept of “functionally important motions,” physics has crossed a significant threshold. ”Functional importance” is both a teleological and a normative concept, and protein physics bids fair to be the crossroads where physics and biology finally encounter each other in a fundamental way.(9)
Another important feature of protein dynamics is the fact that enzymes are not generally thermodynamically isolated, but rather are closely coupled to their cellular environment, whether to a membrane or to the cytosol (the fluid component of the cytoplasm, i.e., water).
This phenomenon—known in the literature by the colorful name of “slaving”—means that a protein’s functional behavior is not determined by its three-dimensional structure alone, but is always to some degree determined by its environment.(10)
In summary, proteins are far from being the static molecular “machines” of popular imagining. Rather, their behavior is dominated by their intrinsic dynamics (frustration) and thermodynamic coupling to their environment (slaving).(11)
We are only beginning to understand how these physical properties affect protein function, but it is already clear that the lock-and-key model we have grown up with is terribly oversimplified and highly misleading in fundamental respects.
The last physical property of cells I wish to mention is cell crowding.
If asked, most people would probably admit that the cytosol is immensely crowded with protein, lipid, and other soft-matter structures (even if many of them are transient).
And yet, the direct consequence of this fact is too often ignored: Considered as a whole, cytoplasm must have physical properties that are very different from those of ordinary liquid water—properties that make of cytoplasm an intermediate state of matter in between a liquid and a solid, like a gel or a liquid crystal.(12)
This is what one would expect on theoretical grounds from the sheer fact of cell crowding, but experimental evidence is also not lacking. For example, relatively large sections of the cell membrane may be excised with no visible effect on the functioning of the cell, and with no leakage of cell contents.(13)
Therefore, the idea most of us carry around in our heads of cytoplasm as a solution dominated by thermal diffusion effects is demonstrably false.
In future installments, I shall be looking at several biologists who take the gel-like character of cytoplasm explicitly into account in their theoretical work. But for now, I will close by simply registering the fact of cell crowding.
It is a fact of immense importance from a physical point of view, and must be taken into account in our search for biological understanding in a way it has not been up until now.
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Considered together, our modern understanding of these three physical properties of life—self-organization of cellular structures, protein dynamics, and cell crowding—makes it abundantly clear that we must retrain our imaginations as we seek to understand how living things work.
What, precisely, that retraining should consist in will be the subject of the remaining installments in this series.
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Part VI: F.E. Yates’s Homeodynamics
(1) Alexei Kurakin, “Order without Design,” Theoretical Biology and Medical Modelling, 2010, 7:12; p. 2.
(2) Alexei Kurakin, “Self-Organization versus Watchmaker: Molecular Motors and Protein Translocation,” BioSystems, 2006, 84: 15–23; p. 17.
(3) Ibid.; pp. 21–22.
(4) Alexei Kurakin, “Self-Organization versus Watchmaker: Stochastic Dynamics of Cellular Organization,” Biological Chemistry, 2005, 386: 247–254; p. 250.
(5) Alexei Kurakin, “Scale-Free Flow of Life: On the Biology, Economics, and Physics of the Cell,” Theoretical Biology and Medical Modelling, 2009, 6:6; p. 20.
(6) At a minimum, one must distinguish between “self-assembly” (or “self-ordering”), which may be described in “downhill” (exergonic) terms, and “self-organization,” which cannot be adequately so described. On this important topic, see Julianne D. Halley and David A. Winkler, “Consistent Concepts of Self-Organization and Self-Assembly,” Complexity, 2008, 14(2): 10–17.
(7) Gregorio Weber, “Energetics of Ligand Binding to Proteins,” Advances in Protein Chemistry, 1975, 29: 1–83; p. 1.
(8) Hans Frauenfelder, et al., “Biological Physics,” Reviews of Modern Physics, 1999, 71 (special issue): S419–S430.
(9) Hans Frauenfelder, et al., “The Energy Landscapes and Motions of Proteins,” Science, 1991, 254: 1598–1603.
(10) Hans Frauenfelder, et al., “Protein Dynamics and Function: Insights from the Energy Landscape and Solvent Slaving,” IUBMB Life, 2007, 59(8–9): 506–512.
(11) For detailed information on protein dynamics, see Hans Frauenfelder, The Physics of Proteins: An Introduction to Biological Physics and Molecular Biophysics, edited by Shirley S. Chan and Winnie S. Chan (Springer, 2010). For more concise summaries, see Hans Frauenfelder, et al., “A Unified Model of Protein Dynamics,” Proceedings of the National Academy of Sciences, USA, 2009, 106: 5129–5134; and Elan Z. Eisenmesser, et al., “Intrinsic Dynamics of an Enzyme Underlies Catalysis,” Nature, 2005, 438: 117–121.
(12) See Katherine Luby-Phelps, “Cytoarchitecture and Physical Properties of Cytoplasm: Volume, Viscosity, Diffusion, Intracellular Surface Area,” in Harry Walter, et al., eds., International Journal of Cytology, Vol. 192: Microcompartmentation and Phase Separation in Cytoplasm (Academic Press, 2000), pp. 189–221; Allen P. Minton “The Influence of Macromolecular Crowding and Macromolecular Confinement on Biochemical Reactions in Physiological Media,” Journal of Biological Chemistry, 2001, 276: 10577–10580; M.A. McNiven, “The Solid State Cell,” Biology of the Cell, 2003, 94: 555–556; and Denys N. Wheatley, “Diffusion, Perfusion and the Exclusion Principles in the Structural and Functional Organization of the Living Cell: Reappraisal of the Properties of the ‘Ground Substance,’” Journal of Experimental Biology, 2003, 206: 1995–1961.
(13) Gerald H. Pollack, Cells, Gels and the Engines of Life (Ebner & Sons, 2001); Chapter 2, pp. 25–37.