Stuart J. Edelstein

Research Activities

My research has been dominated by a long-standing interest in cooperative interactions of proteins and their ligands (see allostery classics), beginning with oxygen binding and the structure of hemoglobin, especially the helical fibers of the sickling mutant, hemoglobin S (beta 6 Glu to Val), for which, with Gene Dykes and Richard Crepeau, we established the 14-strand structure. In field work in Africa, I also studied the impact of sickle cell anemia in rural populations of Nigeria, as described in my 1986 book, THE SICKLED CELL. FROM MYTHS TO MOLECULES (Harvard University Press) [pdf]. In addition, my laboratory worked on the structure and function of tubulin, especially from yeast, as well as microtubule associated proteins.

In later years, research involved detailed modeling of the kinetics of ligand-gated channels, in collaboration with Jean-Pierre Changeux. An allosteric-type mechanistic model incorporating linear free energy relations to describe the effects of ligand binding on interconversions between conformations was developed and applied principally to single channel data of the nicotinic acetylcholine receptor and certain myasthenic mutants. The theory has also been extended to the single binding events that in principle could be recorded using fluorescence correlation methods. A comprehensive view of the subject was presented in our 2005 book NICOTINIC ACETYLCHOLINE RECEPTORS: FROM MOLECULAR BIOLOGY TO COGNITION (The Johns Hopkins University Press): Look inside the book at Amazon.

The complete model incorporates stochastic simulations that can be used to describe the individual events of single ion channels, as well as single binding events. The current version, designated STOIC (for Simulation of Transient Openings in Ionotropic-receptor Channels), was programmed in collaboration with Olivier Schaad to run in the MATLAB environment and is available upon request.

Recent activities have focused on applying the allosteric principles to more complex systems, in collaboration with Nicolas Le Novère at the European Bioinformatics Institue (Cambridge). In particular, we have been investigating the interactions involving calcium/calmodulin-dependent kinase II and more generally the dynamics of the dendritic spines of neurons. In the course of this work, major implications of ligand depletion have been identified and a new measure of cooperativity has been formulated to replace the classical Hill coefficient, which was found to be inappropriate for many of the systems examined.

Looking beyond to behavioral issues, I have also begun to examine how principles of bistability initially derived from allosteric theory can be applied at the neuronal and inter-neuronal levels in the study of simple perceptual phenomena, for example the alternation of images perceived upon examining the two-dimensional project of an ambiguous object, such as the Necker cube (below on left). When the object is rotated, it appears to change direction,as can be observed in the animated version (below on right).

Click here for a spinning necker cube Java applet created with Niels van Galen Last:

What happens with a field of Necker cubes--do they change together? Find out here.