France

Jean-Pierre Changeux

2001 Balzan Prize for Cognitive Neurosciences

Professor Changeux's broad and profound contribution ranges from the fundamental molecular mechanisms of chemical communication in the nervous system to learning and consciousness. In addition to his outstanding experimental work, Professor Changeux has made a theoretical contribution on the epigenesis of neuronal networks by selective stabilisation of developing synapses and on several aspects of cognition.
Jean-Pierre Changeux has established a new direction for the study of cognitive functions by rooting them at the molecular level.

Professor at Collège de France and at Institut Pasteur in Paris, Jean-Pierre Changeux (born in Domont, France, in 1936) is one of the fathers of modern neurobiology. His studies on acetylcholine receptors, isolated in the electric organs of some fish species, have been crucial to clarifying the way in which brain neurons communicate among them. As well as being a first-class molecular and cellular biologist, Changeux is considered a maître à penser, a “humanist of the 21st century”, for his rich personality and for his ability to throw bridges between the life sciences and the humanities, as witnessed by his books.
L’ homme neuronal, (1983), is an example of high-level scientific popularisation and quickly established itself as a classic of neuroscience. His commitment to philosophy is highlighted in his conversations with leading figures of our age, such as the mathematician Alain Connes, in which he discusses the nature of mathematical objects in our brain (in Matière à pensée, 1989), and with the philosopher Paul Ricoeur ( Balzan Prize 1999 for philosophy), in which he debates the relationship between mind and brain (in La nature et la règle, 1998). Finally, his passion for art is displayed in Raison et plaisir (1994) in which he investigates the “cerebral” origin of artistic creation and its enjoyment.

Laudatio

The research of Jean-Pierre Changeux has centred on the fundamental molecular and cellular mechanisms involved in the recognition of chemical signals and their transduction into biological activity. He has studied these mechanisms ranging from the metabolism of bacterial cells to the complex physiological and pharmacological modulation of higher cognitive functions of the brain.

In his early work (1961-1964) as a graduate student, Jean-Pierre Changeux discovered, using a bacterial enzyme, that the interactions between regulatory signal and substrate can be resolved in vitro. This laid down the experimental basis from which he developed the concept of allosteric interaction, which is the communication between two topographically distinct reaction sites of a protein molecule mediated by its conformational change. Jean-Pierre Changeux soon extended this notion to the elementary mechanisms of signal transduction mediating intercellular communication, primarily in the nervous system.

Jean-Pierre Changeux was able to apply the concept of allosteric protein specifically to the receptor for acetylcholine involved in synaptic transmission at the neuromuscular junction. He is responsible for the first identification and the purification of a channel linked neurotransmitter receptor protein, the acetylcholine nicotinic receptor. This was the first membrane receptor molecule that was isolated and characterised. Jean-Pierre Changeux and his group then unravelled the fundamental characteristics of the receptor protein: its elementary physiochemical properties, its pentameric organisation; the first partial N-terminal amino acid sequence of one subunit, which led to the cloning and complete sequencing of the acetylcholine receptor. They also identified the acetylcholine binding site. These results were extended by Jean-Pierre Changeux to neuronal nicotinic receptors in the brain.

As a result of this work Changeux opened up a large new field of investigations in neuroscience. This revolution was rapidly extended from lower vertebrates to the brain of higher vertebrates, including man.

The refined analysis of the acetylcholine receptor was followed in the 1990s by a genetic dissection of its role in higher cognitive functions. Working on the mouse, Jean-Pierre Changeux found that certain mutations at the level of the ion channel lead to hyperactive receptors, which proved to be responsible for autosomal dominant frontal lobe epilepsy in man. Mutations causing loss of function of the AchR result in deficits in cognitive learning and accelerated aging. This approach showed that higher functions like long term memory, attention, emotion and drug dependence are strongly linked to neuronal mechanisms mediated by the nicotinic receptor of acetylcholine.

Jean-Pierre Changeux and his group were the first to develop the concept of “receptor disease” that has now become classical. Following their approach other groups have demonstrated that schizophrenia is related to mutations in a particular subunit of the AchR and that Alzheimer’s disease is also characterized by a deficit in nicotinic receptors.

As a theoretician, one of the most prominent contributions of Jean-Pierre Changeux was the synthesis of processes from molecular and cellular to the highest cognitive levels which he presented in his book L’homme neuronal published in 1983.

In summary, the experimental and theoretical work of Jean-Pierre Changeux throughout the past 40 years has revolutionised neuroscience by firmly rooting the functions of the brain, both at the cellular and at higher levels, in basic molecular mechanisms. Progressively, Jean-Pierre Changeux has moved from the allosteric mechanism he discovered with bacterial regulatory enzymes, to neurotransmitter receptors. He identified the first receptor for the neurotransmitter acetylcholine. From the structural data he gained on the acetylcholine nicotinic receptor protein, its binding sites, ion channel and conformational transitions, he showed that cognitive functions, including learning, reward and conscious states depend on this receptor protein.

In the field of cognition, the original extension of the selectionist scheme to the epigenesis of neuronal networks and to higher brain functions, has inspired a number of theoreticians and experimentalists.