Jean-Pierre Changeux
Encyclopedia
Jean-Pierre Changeux 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.
, 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.
.
During his PhD
training, under the direction of Jacques Monod
and Francois Jacob
, Changeux studied the allosteric regulation
s 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 organ
s (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
.
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 recented 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.
, 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.
s 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.
, 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.
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.
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.
, that explained the cooperativity exhibited by many allosteric proteins, such as hemoglobin)
(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.)
Neuroscience
Neuroscience is the scientific study of the nervous system. Traditionally, neuroscience has been seen as a branch of biology. However, it is currently an interdisciplinary science that collaborates with other fields such as chemistry, computer science, engineering, linguistics, mathematics,...
known for his research in several fields of biology
Biology
Biology is a natural science concerned with the study of life and living organisms, including their structure, function, growth, origin, evolution, distribution, and taxonomy. Biology is a vast subject containing many subdivisions, topics, and disciplines...
, from the structure and function of proteins (with a focus on the allosteric proteins), to the early development of the nervous system
Nervous system
The nervous system is an organ system containing a network of specialized cells called neurons that coordinate the actions of an animal and transmit signals between different parts of its body. In most animals the nervous system consists of two parts, central and peripheral. The central nervous...
up to cognitive functions. Although being famous in biological sciences for the MWC model
MWC model
In biochemistry, the MWC model describes allosteric transitions of proteins made up of identical subunits. It was proposed by Jean-Pierre Changeux based on his PhD experiments, and described by Jacques Monod, Jeffries Wyman, and Jean-Pierre Changeux...
, the identification and purification of the nicotinic acetylcholine receptor
Nicotinic acetylcholine receptor
Nicotinic acetylcholine receptors, or nAChRs, are cholinergic receptors that form ligand-gated ion channels in the plasma membranes of certain neurons and on the postsynaptic side of the neuromuscular junction...
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 DomontDomont
Domont is a commune in the Val-d'Oise department and Île-de-France region of France.-Notable people from Domont:*Bedi Buval footballer*Jean-Pierre Changeux neuroscientist*Yoann Djidonou footballer*Rémi Maréval footballer*Bertrand Ndzomo footballer...
, France
France
The French Republic , The French Republic , The French Republic , (commonly known as France , is a unitary semi-presidential republic in Western Europe with several overseas territories and islands located on other continents and in the Indian, Pacific, and Atlantic oceans. Metropolitan France...
. He entered the École Normale Supérieure
École Normale Supérieure
The École normale supérieure is one of the most prestigious French grandes écoles...
in 1955, where he obtained a Bachelor's degree
Bachelor's degree
A bachelor's degree is usually an academic degree awarded for an undergraduate course or major that generally lasts for three or four years, but can range anywhere from two to six years depending on the region of the world...
(Licence) in 1957 and a Master's degree
Master's degree
A master's is an academic degree granted to individuals who have undergone study demonstrating a mastery or high-order overview of a specific field of study or area of professional practice...
(Diplome d'Études Supérieure) in 1958. He also received his agrégation
Agrégation
In France, the agrégation is a civil service competitive examination for some positions in the public education system. The laureates are known as agrégés...
in natural science the same year. He began his scientific career during his ENS years during summer internships in Banyuls-sur-Mer
Banyuls-sur-Mer
Banyuls-sur-Mer is a commune in the Pyrénées-Orientales department in southern France.-Geography:Banyuls-sur-Mer is neighbored by Cerbère, Port-Vendres, Argelès-sur-Mer and Collioure. The region is known for its wines, such as the sweet wine Banyuls. An aquatic museum with aquarium is located in...
where he identified a new genus of parasitic
Copepod
Copepod
Copepods are a group of small crustaceans found in the sea and nearly every freshwater habitat. Some species are planktonic , some are benthic , and some continental species may live in limno-terrestrial habitats and other wet terrestrial places, such as swamps, under leaf fall in wet forests,...
. He pursued PhD
PHD
PHD may refer to:*Ph.D., a doctorate of philosophy*Ph.D. , a 1980s British group*PHD finger, a protein sequence*PHD Mountain Software, an outdoor clothing and equipment company*PhD Docbook renderer, an XML renderer...
studies at the Pasteur Institute
Pasteur Institute
The Pasteur Institute is a French non-profit private foundation dedicated to the study of biology, micro-organisms, diseases, and vaccines. It is named after Louis Pasteur, who made some of the greatest breakthroughs in modern medicine at the time, including pasteurization and vaccines for anthrax...
under the direction of Jacques Monod
Jacques Monod
Jacques Lucien Monod was a French biologist who was awarded a Nobel Prize in Physiology or Medicine in 1965, sharing it with François Jacob and Andre Lwoff "for their discoveries concerning genetic control of enzyme and virus synthesis"...
and Francois Jacob
François Jacob
François Jacob is a French biologist who, together with Jacques Monod, originated the idea that control of enzyme levels in all cells occurs through feedback on transcription. He shared the 1965 Nobel Prize in Medicine with Jacques Monod and André Lwoff.-Childhood and education:François Jacob is...
, 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
Columbia University College of Physicians and Surgeons
Columbia University College of Physicians and Surgeons, often known as P&S, is a graduate school of Columbia University that is located on the health sciences campus in the Washington Heights neighborhood of Manhattan...
, New-York (1967). He returned to France as attaché to the chair of Molecular Biology held by Jacques Monod
Jacques Monod
Jacques Lucien Monod was a French biologist who was awarded a Nobel Prize in Physiology or Medicine in 1965, sharing it with François Jacob and Andre Lwoff "for their discoveries concerning genetic control of enzyme and virus synthesis"...
. In 1972, he became director of the Unit of Molecular Neurobiology at the Pasteur Institute
Pasteur Institute
The Pasteur Institute is a French non-profit private foundation dedicated to the study of biology, micro-organisms, diseases, and vaccines. It is named after Louis Pasteur, who made some of the greatest breakthroughs in modern medicine at the time, including pasteurization and vaccines for anthrax...
, where he received a professorship in 1975. In 1975, Changeux was elected professor at the Collège de France
Collège de France
The Collège de France is a higher education and research establishment located in Paris, France, in the 5th arrondissement, or Latin Quarter, across the street from the historical campus of La Sorbonne at the intersection of Rue Saint-Jacques and Rue des Écoles...
, 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 functionsCognitive functions
In some forms of psychological testing, particularly those related to the Myers-Briggs Type Indicator, the cognitive functions are defined as different ways of perceiving and judging the world...
.
Allostery
PHD
PHD may refer to:*Ph.D., a doctorate of philosophy*Ph.D. , a 1980s British group*PHD finger, a protein sequence*PHD Mountain Software, an outdoor clothing and equipment company*PhD Docbook renderer, an XML renderer...
training, under the direction of Jacques Monod
Jacques Monod
Jacques Lucien Monod was a French biologist who was awarded a Nobel Prize in Physiology or Medicine in 1965, sharing it with François Jacob and Andre Lwoff "for their discoveries concerning genetic control of enzyme and virus synthesis"...
and Francois Jacob
François Jacob
François Jacob is a French biologist who, together with Jacques Monod, originated the idea that control of enzyme levels in all cells occurs through feedback on transcription. He shared the 1965 Nobel Prize in Medicine with Jacques Monod and André Lwoff.-Childhood and education:François Jacob is...
, Changeux studied the allosteric regulation
Allosteric regulation
In biochemistry, allosteric regulation is the regulation of an enzyme or other protein by binding an effector molecule at the protein's allosteric site . Effectors that enhance the protein's activity are referred to as allosteric activators, whereas those that decrease the protein's activity are...
s 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
MWC model
In biochemistry, the MWC model describes allosteric transitions of proteins made up of identical subunits. It was proposed by Jean-Pierre Changeux based on his PhD experiments, and described by Jacques Monod, Jeffries Wyman, and Jean-Pierre Changeux...
for allosteric proteins. The main ideas behind this theory are: 1) proteins can exist under various conformations in thermal equilibrium
Thermal equilibrium
Thermal equilibrium is a theoretical physical concept, used especially in theoretical texts, that means that all temperatures of interest are unchanging in time and uniform in space...
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
Hemoglobin
Hemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates, with the exception of the fish family Channichthyidae, as well as the tissues of some invertebrates...
.
In his PhD thesis, Changeux suggested that the recognition and transmission of signals by membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
, 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
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
(an idea that would also be developed three decades afterward by Dennis Bray
Dennis Bray
Dennis Bray is an active emeritus professor at University of Cambridge. His group is also part of the Oxford Centre for Integrative Systems Biology...
). He then applied this idea to the post-synaptic membrane of electric organ
Electric organ
In biology, the electric organ is an organ common to all electric fish used for the purposes of creating an electric field. The electric organ is derived from modified nerve or muscle tissue...
s (analog to striated muscle
Skeletal muscle
Skeletal muscle is a form of striated muscle tissue existing under control of the somatic nervous system- i.e. it is voluntarily controlled. It is one of three major muscle types, the others being cardiac and smooth 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
Acetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
. 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
Hemoglobin
Hemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates, with the exception of the fish family Channichthyidae, as well as the tissues of some invertebrates...
.
Nicotinic receptor structure
In 1970, Changeux isolated the nicotinic acetylcholine receptorNicotinic acetylcholine receptor
Nicotinic acetylcholine receptors, or nAChRs, are cholinergic receptors that form ligand-gated ion channels in the plasma membranes of certain neurons and on the postsynaptic side of the neuromuscular junction...
of the eel electric organ
Electric organ
In biology, the electric organ is an organ common to all electric fish used for the purposes of creating an electric field. The electric organ is derived from modified nerve or muscle tissue...
, 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
Shosaku Numa
Shosaku Numa ForMemRS was a Japanese neurobiologist.He graduated from Kyoto University in 1952. He studied at Harvard Medical School with John Lawrence Oncley. He worked at the Max Planck Society with Feodor Felix Konrad Lynen....
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 recented 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 DanchinAntoine Danchin
Antoine Danchin PhD DSc is a French geneticist known for his research in several fields of biology, from the structure and function of adenylate cyclase, to modelisation of learning in the nervous system and the early development of genomics and bioinformatics. He is the Chairman of the startup...
, Changeux proposed a model describing how, during development of the nervous system
Nervous system
The nervous system is an organ system containing a network of specialized cells called neurons that coordinate the actions of an animal and transmit signals between different parts of its body. In most animals the nervous system consists of two parts, central and peripheral. The central nervous...
, 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
Gerald Edelman
Gerald Maurice Edelman is an American biologist who shared the 1972 Nobel Prize in Physiology or Medicine for work with Rodney Robert Porter on the immune system. Edelman's Nobel Prize-winning research concerned discovery of the structure of antibody molecules...
. 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 organElectric organ
In biology, the electric organ is an organ common to all electric fish used for the purposes of creating an electric field. The electric organ is derived from modified nerve or muscle tissue...
s 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
Neuromuscular junction
A neuromuscular junction is the synapse or junction of the axon terminal of a motor neuron with the motor end plate, the highly-excitable region of muscle fiber plasma membrane responsible for initiation of action potentials across the muscle's surface, ultimately causing the muscle to contract...
, the synapse linking the motorneuron to the skeletal muscle
Skeletal muscle
Skeletal muscle is a form of striated muscle tissue existing under control of the somatic nervous system- i.e. it is voluntarily controlled. It is one of three major muscle types, the others being cardiac and smooth 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 DehaeneStanislas Dehaene
Stanislas Dehaene is a professor at the Collège de France, author, and director of INSERM . He has worked on a number of topics, including numerical cognition, the neural basis of reading and the neural correlates of consciousness. Dehaene was one of ten people to be awarded the James S...
, 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.
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.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 MedicineWolf Prize in MedicineThe Wolf Prize in Medicine is awarded once a year by the Wolf Foundation in Israel. It is one of the six Wolf Prizes established by the Foundation and awarded since 1978; the others are in Agriculture, Chemistry, Mathematics, Physics and Arts. The Prize is probably the third most prestigious award...
- 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 PrizeBalzan PrizeThe International Balzan Prize Foundation awards four annual monetary prizes to people or organisations who have made outstanding achievements in the fields of humanities, natural sciences, culture, as well as for endeavours for peace and the brotherhood of man.-Rewards and assets:Each year the...
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 AwardGolden Eurydice AwardThe Golden Eurydice Award is presented for an outstanding contribution, or contributions over a period, in the field of Biophilosophy. It is awarded by the International Forum for Biophilosophy which was established in Belgium by Royal Decree in 1988. Founding members included Herman Van Den...
from International Forum of Biophilosophy - 2007: NAS Award in the NeurosciencesNAS Award in the NeurosciencesThe NAS Award in the Neurosciences is awarded by the U.S. National Academy of Sciences "in recognition of extraordinary contributions to progress in the fields of neuroscience, including neurochemistry, neurophysiology, neuropharmacology, developmental neuroscience, neuroanatomy, and behavioral...
from the National Academy of SciencesUnited States National Academy of SciencesThe National Academy of Sciences is a corporation in the United States whose members serve pro bono as "advisers to the nation on science, engineering, and medicine." As a national academy, new members of the organization are elected annually by current members, based on their distinguished and... - 2008: Neuronal plasticity prize, IPSEN Foundation
- 2008: CINP Pioneer Award
- 2010: Passarow award for «extraordinary achievements in neuropsychiatric research», Los Angeles, 2010.
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 transitionsMWC model
In biochemistry, the MWC model describes allosteric transitions of proteins made up of identical subunits. It was proposed by Jean-Pierre Changeux based on his PhD experiments, and described by Jacques Monod, Jeffries Wyman, and Jean-Pierre Changeux...
, 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 ConnesAlain ConnesAlain Connes is a French mathematician, currently Professor at the Collège de France, IHÉS, The Ohio State University and Vanderbilt University.-Work:...
. (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)