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 is active rather than reactive and that interaction with the environment, rather than being instructive, results in the selection of preexisting internal representations.

Biography
Changeux was born in Domont, France. 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 Francois 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 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.

Scientific achievements
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.

Allostery
During his PhD training, under the direction of Jacques Monod and Francois 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 explain 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 than the allosteric regulations of enzymes. More than forty years of research would follow, mainly focussed on nicotinic acetylcholine receptors (see below). 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 explained 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 during decades on hemoglobin.

Nicotinic receptor structure
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 The isolation of the receptor was also later reported by Ricardo Miledi. The improvements of purification methods developed in the group allowed to propose 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.

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. The molecular basis of ionic selectivity were are also identified in the transmembrane domain. The structure of the binding site for the acetylcholine and nicotine was located at the interface between adjacent subunits.

The quest of Changeux for the structure of the nicotinic receptor culminated with the publication of the structure, at atomic resolution, of a bacterial homolog in the open conformation supporting the idea of a symmetrical concerted opening.

Stabilization of synapses by neuronal activity
In 1973, together with Philippe Courrège and Antoine Danchin, Changeux proposed a model describing how, during development of the nervous system, the activity of a network could cause the stabilization or regression of the synapses involved and illustrated it with the neuromuscular junction. This model is effectively the precursor of the "neural Darwinism" theory further promoted by Gerald Edelman. Changeux later extended and illustrated further this idea. During the 1970s, he tried to document this phenomenon, either by studying mutant animals or by experimental denervation.

Nicotinic receptor function
While until the 1990s, Changeux's group studied the structure of the nicotinic receptor present in electric organs of electric eel and torpedo, the investigations of the physiological role of those receptors were mostly focussed on two model systems: the nicotinic receptors of the neuromuscular junction, the synapse linking the motorneuron to the skeletal muscle, and the nicotinic receptors of the brain, notably in relation with nicotine addiction.

From the mid-1980s, the group studied the compartimentalisation of the muscle cell upon development, as a model of synaptogenesis and in relation with the theoretical work on epigenesis. In particular, the group focussed on the accumulation of nicotinic receptors in the post-synaptic region upon development, concommitent to a switch of receptor identity. They were able to decrypt the different signalling pathways involved in the response to synaptic activity, showing that the accumulation resulted from an inhibition of gene transcription outside the synaptic region due to electrical activity triggering an uptake of calcium and activation of PKC,   and a stimulation of gene transcription at the synapse by the calcitonin gene-related peptide (CGRP) activating PKA   and the ARIA (heregulin) activating tyrosine kinase cascades.

The 1990s saw the progressive shift of interest of Changeux from the neuromuscular junction to the nicotinic receptors expressed in the brain. Among the notable achievements of the group is the discovery that neuronal nicotinic receptors are highly permeable to calcium - which explains the positive effect of nicotinic receptors on the release of many neurotransmitters in the brain - but also that calcium is an allosteric modulator of those receptors (This was also discovered independently by the group of John Dani ). The group later identified the allosteric binding sites of calcium.

By the mid-1990s, Changeux concentrated most of his interest on the function of nicotinic receptors in the basal ganglia and in particular the mesencephalic dopaminergic system. Using mice deleted for nicotinic receptor genes, the group characterised the types of receptor subunits present in the dopaminergic cells  and identified the receptors mainly responsible of the dependence to nicotine, formed by the subunits α4, α6 and β2.

Modeling cognition
From the mid-1990s, Changeux pursued an activity of computational modeling in order to investigate the basis of cognitive functions. This research did not generally involve his group at the Pasteur institute, but was mainly performed in collaboration with Stanislas Dehaene, now leading the INSERM-CEA Cognitive Neuroimaging Unit. They modeled for instance the acquisition of song recognition in birds or the development of numerical abilities. More recently, Dehaene and Changeux developed a model for access to consciousness based on a brain-wide recruitment of networks of neurons with long-range axons, the global workspace.

Professional and non-scientific activities
Changeux has headed the National Advisory Committee on Bioethics in France from 1992 to 1998. He organised a scientific conference on the topic, that led to a book he edited, fondements naturel de l'ethique.

He is also on the Board of Scientific Governors of The Scripps Research Institute, an independent nonprofit institute focusing on biomedical research.

Changeux is passionate about art, and in particular graphical arts. Beside his academic career, he has organised several expositions: "De Nicolo Dell'Abate à Nicolas Poussin: Aux Sources Du Classicisme" (Meaux), "La Lumière au siècle des lumières" (Nancy), "Passions de l"âme" (Meaux) and co-organised (with Jean Clair) a major exposition on art and sciences in Paris "l'Ame au corps".

Changeux has also chaired the inter-ministry commission for the conservation of the French artistic heritage since 1989, and has been member of the scientific council of the International Agency of museums since 2007.

Scientific prizes and awards

 * 1977: Alexandre-Joannidès prize of the French Academy of Sciences
 * 1978: Gairdner Foundation International Award
 * 1982: Wolf Foundation Prize in Medicine
 * 1982: prize Richard-Lounsbery of the US Academy of Sciences and the French Academy of Sciences
 * 1983: literacy prize Broquette-Gonin of the French academy for the "l'Homme neuronal"
 * 1985: Ciba Geigy Drew Award in Biomedical Research
 * 1986: prize F.-O- Schmitt of the Neursosciences Research Institute.
 * 1988: Rita-Levi-Montalcini prize of the Fidia Foundation
 * 1990: Bristol-Myers-Squibb prize of the Neurosciences Research Institute.
 * 1991: Carl-Gustav-Bernhard medal of the Swedish Academy of Science
 * 1992: Science for Art, Prix d'Honneur LVMH
 * 1992: International Prize Amedeo e Frances Herlitzka for Physiological Sciences
 * 1992: Gold-medal of the French CNRS.
 * 1993: Louis-Jeantet prize for Medicine
 * 1993: Thudichum medal, Biochemical Society
 * 1994: Goodman and Gilman Award in drug receptor pharmacology
 * 1994: Camillo Golgi medal, Accademia Nazionale dei Lincei
 * 1994: Sir Hans Krebs medal, FEBS
 * 1996: Max-Delbrück Medal in Molecular Medicine
 * 1997: Great prize of the Foundation for Medical Research, Paris
 * 1997: Prize Jean-Louis Signoret in Neuropsychology, Ipsen Foundation
 * 1998: Prize Emanuel Merck in Chemistry, Darmastadt
 * 1999: Linus Pauling medal, Stanford, US
 * 1999: Eli Lilly award in preclinical Neuroscience, European College of Neuropsychopharmacology
 * 2000: Langley Award for basic research on nicotine and tobacco, Washington
 * 2001: Balzan Prize for Cognitive Neurosciences
 * 2002: American Philosophical Society’s Karl Spencer Lashley Award in neuroscience
 * 2005: Lewis Thomas Prize for Writing about Science
 * 2006: Dart/NYU Biotechnology Award in Basic Biotechnology
 * 2006: Golden Eurydice Award from International Forum of Biophilosophy
 * 2007: NAS Award in the Neurosciences from the National Academy of Sciences
 * 2008: Neuronal plasticity prize, IPSEN Foundation
 * 2008: CINP Pioneer Award
 * 2010: Pasarow Award for "Extraordinary achievements in neuropsychiatric research", Los Angeles

Academic memberships and honorary degrees
Deutsche Akademie der Naturforscher Leopoldina zu Halle (Pharmacology), 1974 ; Académie de Médecine de Turin, 1976 ; National Academy of Sciences, Washington (US) (foreign associate), 1983 ; Royal Academy of Sciences, Stockholm, (Sweden) (foreign member), 1985 ; Académie des Sciences, Paris, 1988 ; Académie Royale de Médecine de Belgique (Bruxelles) (foreign honorary member), 1988 ; Academia Europaea (founding member), 1988 ; American Academy of Arts and Sciences, Boston, (US) (foreign member), 1994 ; Romanian Academy of Medical Sciences, Bucarest (foreign member), 1996 ; Institute of Medicine of the National Academies, Washington, (US) (foreign associate), 2000 ; Istituto Veneto di Scienze, Lettere Ed Arti, Venezia (Italy), 2001 ; Hungarian Academy of Sciences, Budapest (foreign member associate), 2004 ; European Academy of Sciences, Bruxelles (member), 2004 ; International Academy of Humanism; Académie Royale des Sciences, des Lettres & des Beaux-Arts de Belgique (foreign member), 2010; Accademia Nazionale dei Lincei, Rome, (Italy) (foreign member), 2010.

Doctor honoris causa : Universities of Torino, Italy, 1989 ; Dundee, Scotland, 1992 ; Geneva, Switzerland, 1994 ; Stockholm, Sweden, 1994 ; Liège, Belgium, 1996 ; Ecole Polytechnique Fédérale of Lausanne, Switzerland, 1996 ; University of Southern California, Los Angeles, US, 1997 ; Bath, UK, 1997 ; Montréal University, Canada, 2000 ; The Hebrew University of Jerusalem, Israel, 2004 ; Ohio State University, Columbus, US, 2007; University of Buenos Aires, Argentina, 2010.

Honorary member of Neurosciences Research Program, MIT and Rockefeller University (US), since 1984; Honorary member of the Japanese Biochemical Society, Sendai, Japan, 1985 ; Honorary member of the American Neurology Association, 1988 ; Honorary member of University College London, 1990 ; Membre d'honneur à titre étranger de la Société Belge de Neurologie, Bruxelles, 1991 ; Member of European Molecular Biology Organization.

Non-scientific honors
Grand Officier dans l’Ordre de la Légion d'Honneur, 2005; Grand-Croix dans l'Ordre National du Mérite 1995 ; Commandeur dans l'Ordre des Arts et des Lettres, 1994.

Scientific publications of historical significance

 * (in which Jacques Monod, Jeffries Wyman and Jean-Pierre Changeux presented the concerted model of allosteric transitions, that explained the cooperativity exhibited by many allosteric proteins, such as hemoglobin)


 * Changeux J.-P., Kasai M., Huchet M., Meunier J.-C. (1970). Extraction à partir du tissu électrique de gymnote d'une protéine présentant plusieurs propriétés caractéristiques du récepteur physiologique de l'acétylcholine. C. R. Acad. Sci. 270D: 2864-2867. (the first purification of a neurotransmitter receptor. Since the article is in French, most people quote the description of the toxin that allowed the receptor to be identified:


 * (In which the authors develop a formal model of synapse selection, precursor of the "neural darwinism". This is the original work, although most people quote the subsequent review [better suited to a non-specialist audience and presenting the biological context]: Changeux JP, Danchin A (1976) Nature, 264 (1976) 705—712.)

Books by Jean-Pierre Changeux

 * Changeux, Jean-Pierre. (2008) Du vrai, du beau, du bien : Une nouvelle approche neuronale
 * Changeux, Jean-Pierre; Stuart Edelstein. (2004) Nicotinic Acetylcholine Receptors: From Molecular Biology to Cognition
 * Changeux, Jean-Pierre. (2002) L'homme de verite (2004 The physiology of truth)
 * Changeux, Jean-Pierre; Paul Ricœur. (1998) Ce qui nous fait penser (2002 What Makes Us Think. A Neuroscientist and a Philosopher Argue About Ethics, Human Nature, and the Brain )
 * Changeux, Jean-Pierre. (1994) Raison et plaisir
 * Changeux, Jean-Pierre; Alain Connes. (1989) Matière à pensée (1995 Conversations on Mind, Matter and Mathematics)
 * Changeux, Jean-Pierre. (1983) L'homme neuronal (1985 Neuronal Man: The Biology of Mind)