Diffusion theory, the cell and the synapse

The possibility exists that the cell internum is far more highly organised right down to the molecular level than was hitherto appreciated, to the point where ideas of a relatively solid-state chemistry model have been entertained (Coulson, R.A., 1993. The flow theory of enzyme kinetics—a role of solid geometry in the control reaction velocity in live animals. Int. J. Biochem. 25, 1445–1474). This contrasts sharply with the traditional dogma that diffusion is the mechanism by which molecules interact within an aqueous solution of the cell internum, although it should have been clear from an early stage that diffusion could not play other than a very resticted role in metabolic regulation. When physicists began to question certain aspects of the fundamental Law of Heat Conductance formulated over 170 years ago by Fourier, Diffusion Theory was also implicated (Maddox, J., 1989. Heat conductance is a can of worms. Nature 338, 373), and application of Fickʹs Laws of Diffusion to living systems criticised (Agutter P.S., Malone, P.C., Wheatley, D.N., 1995. Intracellular transport mechanisms: a critique of diffusion theory. J. Theoret. Biol. 176, 261–272). While we have argued (Wheatley, D.N., Malone, P.C., 1993. Heat conductance, diffusion theory and intracellular metabolic regulation. Biol. Cell 79, 1–5) that diffusion cannot be prevented from occurring, we found that, irrespective of whether it was a valid theory, diffusion was of little relevance in most actively metabolising cell systems. However, diffusion is still perceived as essential for interacting molecules to demonstrate their specificities. Any new model of the internal state of the living cell has to resolve this dilemma. The question also relates to molecular movement and ligand–receptor interactions outside the cell. In looking at this situation, attention was paid to one site in the body in which diffusion has long been assumed to be essential, namely in the passage of the chemical transmitter between one neurone and the next across the synaptic cleft. A detailed examination of this assumption has helped to identify one possible place in which the importance of diffusion over a distance of no more than 20–30 nm occurs, although objections to diffusion being involved have been raised. The outcome, however, only re-enforces the conviction that diffusion has little role in metabolic activity and is normally ‘assistedʹ in almost all aspects of cell physiology.