Beyond Cell Toons

Abstract

In the roadrunner cartoons, the unlucky coyote, in hot pursuit of the roadrunner, frequently finds himself running off the edge of a precipice. In sympathy with the coyote's plight, the laws of physics suspend their action. Gravity waits to exert its force until the coyote realizes his situation and resigns himself to the inevitable. Only then does the coyote fall, miraculously surviving the near-disaster without serious damage. What does this have to do with cell biology at the turn of the millennium? Blame it on JCS's Caveman or at least the infectiousness of the troglodyte's point of view. But it strikes this Editor that for much of cell biology, no less than for the roadrunner, the laws of physics are seemingly suspended. Pick up any contemporary text book or review article and look at the cartoons (diagrams) that grace the pages. You will find diagrams replete with circles, squares, ellipsoids and iconic representations of molecular components, supramolecular assemblies or membrane compartments. Arrows define signal cascades, pathways of transport and patterns of interaction. Even better, check out any of the supplementary instructional CDs that accompany text books and view the animations. You will see cell toons - molecules moving on smooth trajectories to interact with their partners, assembling into cellular machinery or arriving at cellular destinations. They all seem to know where to go and what to do in their cell toon life. It doesn't matter whether we are talking about DNA replication, protein synthesis, mitochondrial respiration, membrane trafficking, nuclear import, chromatin condensation or assembly of the mitotic spindle to mention just a few examples. In each case, the process unfolds before us as a molecular ballet choreographed by a hidden director. Or should I say anonymous animator. Please don't get me wrong. Cartoon diagrams are a necessary part of science. They help us to form and communicate concepts. Adages such as ‘a picture is worth a thousand words’ do not come into existence for nothing. Further, simplification is necessary to sharpen Occam's razor. Science progresses faster if a hypothesis is honed to the point where it can be readily refuted. Of course, it is best to be right. Next best is to be wrong. But the worst thing that can be said about a concept is that it is so hedged or ambiguous that it cannot even be wrong. Cartoons are invaluable in presenting clear alternatives. And cartoons, by definition, do not attempt to portray reality. We understand and accept that they deliberately omit details which may be important in some other context but which are extraneous to the story line. We do not have to know how the coyote recovers from his disastrous fall. It is sufficient that he resumes the chase. Likewise, much of Cell Biology can satisfactorily be ‘explained’ in terms of the behavior of toons. My thesis for this essay is that cell biology at the turn of the millennium has, for the first time, the real opportunity to burst the frames of the cartoons. The field has progressed to the point where the maxim that cells obey the laws of physics and chemistry can be made more than a creed. The time is approaching for the mystery of the hidden directornymous animator to be dispelled. What is driving this new orientation and what is required to bring it to fruition? Advances in structural biology provide part of the explanation. Atomic structures have been determined for a large variety of proteins, with the number increasing on a daily basis. Structural genomics will succeed genomics. It is possible to foresee that in the not too distant future atomic structures will be known for most if not all the major proteins in a cell. Not only individual proteins but supramolecular assemblies as complex as the ribosome have yielded to structural analysis. Of course, structures per se are static entities, but biology has taught that function is inherent in structure. Knowledge of molecular structures has provided atomic explanations for ligand binding, allosteric interaction, enzymatic catalysis, ion pumps, immune recognition, sensory detection and mechano-chemical transduction. When combined with kinetics, structural biology provides the chemical bedrock of cell biology. But the bedrock of structural biology, while necessary for the new cell biology, is almost certainly not sufficient. A major gap is in understanding the complex properties of self-organizing systems. Cells are ensembles of molecules interacting within boundaries. Some of the molecules are organized into supramolecular assemblies that have been likened to molecular machines. Examples include multi-enzyme complexes, DNA replication complexes, the ribosome and the proteasome. Understanding the operation of these molecular machines in chemical and physical terms is a major challenge in that they display exotic behavior such as solid-state channeling of substrates, error-checking, proof-reading, regulation and adaptiveness. Nevertheless, the conceptual basis for their formation is thought to rest on well-established principles: namely, the equilibrium self-assembly of molecular components whose specific affinities are inherent in their 3-D structure. However, other aspects of cellular organization manifest properties beyond self-assembly. The cytoskeleton, for example, is a steady-state system which requires the continuous input of energy to maintain its organization. It displays emergent properties of self-organization, self-centering, self-polarization and self-propagating motility. Membrane compartments such as the endoplasmic reticulum, the Golgi apparatus and transport vesicles provide additional examples of cellular organization dependent upon dynamic processes far from equilibrium. A further level of complexity is introduced by the fact that the self-organization of one system, such as membrane compartments, may be dependent upon another, such as the cytoskeleton. A challenge for the new cell biology is to go beyond ‘toon’ explanations, to understand the emergent, self-organizing properties of interdependent systems. It is likely that an adequate response to this challenge will be multidisciplinary, involving approaches not normally associated with mainstream cell biology. We are likely to be in for a heavy dose of biophysics, computer modeling and systems analysis. A serious problem will be to identify functional levels of decomposition and reconstitution. Because of the microscopic scale, thermal energy, randomness and stochastic processes will be an intrinsic part of the landscape. Brownian motions may present a Damoclean double edge. They are commonly thought to be responsible for the degradation of order into disorder. But, counterintuitively, random thermal processes may also provide the raw energy which, if biased by energy-dependent molecular switches and motors, generates order from disorder. Non-deterministic processes and selection from among alternative pathways may be a common strategy. Fluctuation theory, probabilistic formulations and rare events may underpin the capacity of molecular ensembles to ‘evolve’ into ordered configurations. Further, biological properties such as error-checking and adaptiveness imply an ‘intelligence’, which suggests that the systems analysis may have ‘software’ as well as ‘hardware’ dimensions. Molecular logic may be non-deterministic, ‘fuzzy’ and able to ‘learn’. The evolvability of the system may itself be an important consideration in understanding the design principles. The belief that cells obey the laws of physics and chemistry means that, in terms of the molecular ballet, the director is not only hidden - he doesn't exist. One is tempted to say that the challenge is to understand how the ballet came to be self- choreographed. But even this formulation misses the point that the individual dancers have no definite positions on the stage. Organization in the cell is a continuity of form, not individual molecules. The challenge is to understand how the ensemble is able to perform the dance with chaotic free substitution.