Wanted: A Positive Control for Anomalous Subdiffusion

Abstract

Much work is being done on anomalous subdiffusion in the plasma membrane, cytoplasm, and nucleus of cells, and in model systems. The main questions are whether diffusion is anomalous or normal, the value of the exponent if diffusion is anomalous, the ergodicity, and interpretation in terms of mechanisms. The field is controversial, especially the hypothesis that crowding causes anomalous subdiffusion. There are two consensus views on this hypothesis, unfortunately contradictory (Hoefling and Franosch, Phys Rev Lett 2007; Dix and Verkman, Ann Rev Biophys 2008). The experimental evidence on both sides has a major limitation: those arguing against anomalous subdiffusion have no positive control and those arguing for anomalous subdiffusion have no calibration standard. So it would be useful to have an experimental standard for anomalous subdiffusion, one able to cross-calibrate SPT, FCS, FRAP, and PGSE NMR measurements. Several requirements apply. The anomalously diffusing particle must be detectable by both fluorescence and NMR. Diffusion must be anomalous over the length and time scales of all these methods, several micrometers and seconds for the optical measurements, and longer lengths for most PGSE measurements. The length scale is fundamental; the time scale can be tuned via the viscosity of the medium. The standard ought to be simple, reproducible, and commercially available. The standard must be theoretically well understood, with a known anomalous subdiffusion exponent, ideally readily tunable. Among the candidate experimental systems for SPT are the random walk of excitons on a large-scale percolation cluster, as in the classic experiments of Kopelman; single-file diffusion in pores; transient anomalous self-diffusion due to binding of particles in arrays of laser traps or transcription factors in DNA arrays; and computer-driven physical trajectories in which a stable fluorophore is moved by a piezo stage. (Supported by NIH grant GM038133)