Jean-Pierre Changeux

Jean-Pierre Changeux (born 6 April 1936) is a French neuroscientist known for his research in several fields of biology, from the structure and function of proteins (with a focus on the allosteric proteins), to the early development of the nervous system up to cognitive functions.

Although being famous in biological sciences for the MWC model, the identification and purification of the nicotinic acetylcholine receptor and the theory of epigenesis by synapse selection are also notable scientific achievements.

Changeux is known by the non-scientific public for his ideas regarding the connection between mind and physical brain.

As put forth in his book, Conversations on Mind, Matter and Mathematics, Changeux strongly supports the view that the nervous system functions in a projective rather than reactive style and that interaction with the environment, rather than being instructive, results in the selection amongst a diversity of preexisting internal representations.

Changeux was born in Domont, France to Marcel Changeux and Jeanne Benoît.

He entered the École Normale Supérieure in 1955, where he obtained a bachelor's degree (Licence) in 1957 and a master's degree (Diplome d'Études Supérieure) in 1958.

He also received his agrégation in natural science the same year.

He began his scientific career during his ENS years during summer internships in Banyuls-sur-Mer where he identified a new genus of parasitic

Copepod.

He pursued PhD studies at the Pasteur Institute under the direction of Jacques Monod and François Jacob, and gained his doctorate in 1964.

Changeux then left France for postdoctoral studies first at the University of California Berkeley (1965–1966) then at Columbia University College of Physicians and Surgeons, New York (1967).

He returned to France as attaché to the chair of Molecular Biology held by Jacques Monod.

In 1967, Changeux extended the MWC model to bi-dimensional lattice of receptors (an idea that would also be developed three decades afterward by Dennis Bray ).

He then applied this idea to the post-synaptic membrane of electric organs (analog to striated muscle).

His team demonstrated the existence of several interconvertible states for the nicotinic receptor, resting, open and desensitized, displaying different affinities for the ligands, such as the endogenous agonist acetylcholine.

The transitions between the states followed different kinetics, and those kinetics plus the differential affinities sufficed to explain the shape of the post-synaptic potential.

A full mechanistic model of the nicotinic receptor from striated muscle (or electric organ) was to be provided much later, when Changeux collaborated with Stuart Edelstein, another specialist of allostery, who worked decades on hemoglobin.

In addition to the allosteric modulation of the channel gating by the agonists, many other regulations of the ligand-gated ion channels activity have since been discovered.

The modulators bind to a variety of allosteric sites, whether on the agonist binding sites, other binding sites at the subunit interfaces, on the cytoplasmic part of the protein or in the transmembrane domain.

The concept of an allosteric pharmacology for ion channels was developed over the years.

In addition to the well known GABAA receptor positive allosteric modulators (such as benzodiazepines and barbiturate drugs), one can find antiparasitic drug such as ivermectin and glutamate receptor modulators used against Alzheimer's disease such as aniracetam.

In 1970, Changeux isolated the nicotinic acetylcholine receptor of the eel electric organ, the first ever isolated membrane pharmacological receptor, that he was able to identify thanks to the properties of a snake toxin, which was purified by Taiwanese researchers CY Lee and CC Chang.

The isolation of the receptor was also later reported by Ricardo Miledi.

The improvements of purification methods developed in the group allowed the proposition that the receptor was a pentameric protein, a finding quickly confirmed by the team of Arthur Karlin.

The group of Changeux was among the firsts to elucidate the primary structure of the subunits of the receptor, in parallel with the group of Shosaku Numa and Stephen Heinemann.

In 1972, he became director of the Unit of Molecular Neurobiology at the Pasteur Institute, where he received a professorship in 1975.

In 1975, Changeux was elected professor at the Collège de France, chair of Cell Communications, position that he held until 2006.

Changeux is author of more than 600 scientific articles and several books, technical or for general audience.

All his scientific career, Changeux has been faithful to a handful of scientific questions, at molecular, cellular and brain levels.

If one needs to seek a unifying theme to all of them, it is the conviction that selection is the basis of life processes, rather than instruction.

While started as separate lines of investigations, all the research threads were tied in the recent decades within the study of allosteric mechanisms as a basis of for the involvement of nicotinic receptors in cognitive functions.

During his PhD studies in the laboratory of Jacques Monod and François Jacob, Changeux studied the allosteric regulations of enzymes, that is the modulation of their activity by compounds different from their substrates.

This work led to the development of the model of concerted transitions for allosteric proteins.

The main ideas behind this theory are: 1) proteins can exist under various conformations in thermal equilibrium in the absence of regulators. The allosteric regulators merely shift the equilibrium between the conformations, stabilizing the ones for which they display the highest affinity, and 2) all the subunits of a symmetrical multimeric protein exist in the same conformation, the transition taking place in a concerted fashion.

The resulting model explains the observed cooperativity without a progressive change of biophysical parameters.

This conceptual framework is still the principal model used to explain the function of cooperative proteins such as hemoglobin.

In his PhD thesis, Changeux suggested that the recognition and transmission of signals by membrane, and in particular by synapses, could use the same mechanisms as the allosteric regulation of enzymes.

More than forty years of research would follow, mainly focussed on nicotinic acetylcholine receptors (see below).

Throughout the 1980s and 1990s, molecular biology technics were used to decipher the tertiary and quaternary structures of the receptor.

The location of the ionic pore was identified, made up of the second transmembrane segment, as shown also later by the groups of Shosaku Numa and Ferdinand Hucho.