Mechanisms of intracellular transport

Although it is conventional to attribute intracellular movements of macromolecules as well as small solutes to ‘diffusion’, the dynamic, self-sustaining organisation of the cell internum and the incessant flux of solvent strongly suggest that non-random processes override the effects of Brownian motion on scales greater than circa 0.1-0.2 microns. TMBG has been involved in a critical (historical and mathematical) re-evaluation of the diffusion concept in biology and work is in progress towards the establishment of more satisfactory mathematical models for intracellular transport processes.

(a) Agutter, P. S , Malone, P. C. & Wheatley, D. N. (2000) Diffusion theory in biology: last bastion of mechanistic materialism? J Hist Biol 33, 71-111.

Abstract: Diffusion theory explains in physical terms how materials move through a medium, e.g. water or a biological fluid. There are strong and widely acknowledged grounds for doubting the applicability of this theory in biology, although it continues to be accepted almost uncritically and taught as a basis of both biology and medicine. Our principal aim is to explore how this situation arose and has been allowed to continue seemingly unchallenged for more than 150 years. The main shortcomings of diffusion theory will be briefly reviewed to show that the entrenchment of this theory in the corpus of biological knowledge needs to be explained, especially as there are equally valid historical grounds for presuming that bulk fluid movement powered by the energy of cell metabolism plays a prominent note in the transport of molecules in the living body. First, the theory's evolution, notably from its origins in connection with the mechanistic materialist philosophy of mid nineteenth century physiology, is discussed. Following this, the entrenchment of the theory in twentieth century biology is analyzed in relation to three situations: the mechanism of oxygen transport between air and mammalian tissues; the structure and function of cell membranes; and the nature of the intermediary metalbolism, with its implicit presumptions about the intracellular organization and the movement of molecules within it. In our final section, we consider several historically based alternatives to diffusion theory, all of which have their precursors in nineteenth and twentieth century philosophy of science.

Agutter, P. S. & Wheatley, D. N. (2000) Random walks and cell size. BioEssays 22, 1018-1023. PMID: 1105647

Abstract: For many years, it has been believed that diffusion is the principle motive force for distributing molecules within the cell. Yet, our current information about the cell makes this improbable. Furthermore, the argument that limitations responsible for the relative constancy of cell size--which seldom varies by more than a factor of 2, whereas organisms can vary in mass by up to 10^24--are based on the limits of diffusion is questionable. This essay seeks to develop an alternative explanation based on transport of molecules along structural elements in the cytoplasm and nucleus. This mechanism can better account for cell size constancy, in light of modern biological knowledge of the complex microstructure of the cell, than simple diffusion.

Agutter, P. S., Malone, P. C. & Wheatley, D. N. (1995) Intracellular transport mechanisms: a critique of diffusion theory. J. Theor. Biol. 176, 261-272. PMID: 7475114

Abstract: It is argued that Brownian motion makes a less significant contribution to the movements of molecules and particles inside cells than is commonly believed, and that the numbers of similar molecules and particles within any near-homogeneous subcompartment of the cell internum are insufficient to justify the statistical assumptions implicit in the derivation of the diffusion equation. For these reasons, it is contended that, contrary to accepted opinion, diffusion theory cannot provide an explanation for intracellular transport at the molecular level. Although attempts have been made to adapt diffusion theory to complex media, the conclusion is that none satisfactorily overcomes the problem of applying the theory to cell biology. However, the heuristic influence of the theory on cellular biophysics and physiology is noted, and possible alternative frameworks for interpreting the valuable experimental data obtained from such studies are outlined.

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