Biography
I was born on December 1st, 1943 in Cairo (Egypt). I went to the Collége des frères in Cairo and then to Nahalal agricultural high school in Israel. Afterwards, I pursued graduate studies at the Hebrew University of Jerusalem in Israel and at Paris VI University (1971) in France. After various post-doctorates from 1973 to 1980 at Cambridge University, Oslo University and finally the McGill University in Montreal , I settled down in France. In 1986, I took over from Alexandre Minkowski as director of INSERM unit U29 ” Neurobiology and Pathophysiology of development” at Cochin hospital in Port Royal.
In 1999, I founded and headed the Neurobiology Institute of the Mediterranean (Inmed) in Marseille. I currently lead a research group and two biotech companies: Neurochlore that aims to understand and treat autism and B&A Therapeutics that aims to understand and treat Parkinson’s disease.
L’Institut de Neurobiologie de la Méditerranée The architectural blueprint of the Inmed Building, built by INSERM, were performed by the Norwegian Snohetta architectural group which is also behind the construction of the library of Alexandria and the Oslo Opera. The institute hosts more than 130 researchers and technicians, and many postdocs from over the world. The institute also houses a business incubator for drug development and therapeutic approaches, an association which aim is dissiminating science (Tous Chercheurs) and a collection of sculptures and paintings I acquired and collected throughout my career. |
Awards
- 2000 Grand Prix Milken de la fondation Américaine de l’épilepsie
- 2002 Grand prix de la Santé de l’EDF
- 2006 prix de la fondation Rotary de France
- 2009 Grand Prix de l’INSERM
- 2009 Docteur Honoraire de l’Université de Liège (Belgique)
- 2010 Grand prix de la société Européenne de l’épilepsie
- 2012 Grand prix du FNRS de Belgique
Research
Brain maturation
In the late 80’s, my colleagues and I discovered that immature neurons, at an early stage of their development, have a higher concentration of intracellular chloride. The consequence of this is that the gamma-aminobutyric acid (GABA), which is transmitted by the action of chloride fluxes, excites immature neurons, while it inhibits adults ones. But, GABA is the principal transmitter of cerebral inhibition in the adult brain and the target of numerous antiepileptics, anxiolytics and anesthetic molecules, such as benzodiazepines. Thus, these agents consumed by a pregnant woman have opposite effects on the neurons of the mother and the embryo, which can have important clinical implications.
Then, we demonstrated that shortly before delivery, the hormones released by the mother prepare the fetus for birth by reducing intracellular chloride, which causes a decrease in neuronal activity and a kind of anesthesia. This increases the resistance of neurons to childbirth related complications and in particular to anoxic (lack of oxygen) and traumatic events.
We also made the first in utero central neuron recordings on primates and discovered the first “patterns” of neural networks discharge. Thus, we provided a general diagram of the neuronal activity maturation sequence.
These findings, and the conceptual advances that they allow, highlight the importance of the environment in brain development and that alterations of these sequences could have major consequences in terms of public health.
Epilepsies and stroke
My team and I have made major conceptual advances in the understanding of epilepsy and, in particular, temporal lobe epilepsy, which in itself only constitutes a large part of the types of epilepsy that does not respond to treatments. We were the first to develop the animal model that mimics the best electro-graphic, clinical and histopathological signatures of this type of epilepsy. We have also shown that the administration of a molecule, kainic acid (a structural analogue of the isolated glutamic acid from the red seaweed Digenea simplex), generates seizures associated with lesions in brain regions sensitive to crises, followed by a reorganization of the neural network and the formation of new connections between neurons.
In other words, after injury, the brain forms new connections whose properties will contribute to the expression of the syndrome. The neurodegenerative process is a continuous process with a “reactive plasticity” that plays a central role in causing the syndrome. Thus, “the crisis leads to the crisis” through a cascade: crisis, injury, budding, formation of new synapses and genesis of new crises. These observations have been, for the most part, confirmed on humans and the concept of reactive plasticity is a focus of current studies. Especially since this reactive plasticity seems to operate in other neurological diseases, and particularly in the aftermath of episodes of stroke.
Neurochlore: understanding and treating developmental brain disorders
In 2011, the discovery of the potential beneficial action of Bumetanide, a diuretic, on autism symptoms led us, Eric Lemonnier, Nouchine Hadjikhani and I, to found Neurochlore, a young Start-Up hosted at Inmed. This Start-Up is leading clinical trials necessary to obtain marketing authorization for Bumetanide for the treatment of autism. Neurochlore is dedicated to both drug development and basic research to understand the molecular mechanisms of autism and the mechanisms of action of Bumetanide.
For more information about Neurochlore
For more information on clinical trial
B&A Therapeutics: understanding and treating Parkinson’s disease
Parkinson’s disease (PD) is caused by the degeneration of dopaminergic neurons of the substantia nigra that innervate the striatum. The drug treatment of PD is based essentially on the compensation of the lack of dopamine by the administration of a dopamine precursor, L-dopa. Still, this approach has its limits including a progressive loss of efficiency and dyskinesias that occur every few years. It is therefore essential to find new therapeutic approaches not based on the dopaminergic system and to this end determine the effects of the lack of dopamine in striatal neurons. In a recent study, we found that the main population of neurons in the striatum, the medium-sized spiny neurons (MSNs), which constitute 95% of striatal neurons, generate giant GABAergic activities in two mouse models of PD. These currents are a signature of the disease as L-Dopa as the lesion of the subthalamic nucleus in humans attenuate disease also eliminate these currents. Therefore, drugs that block these giant currents might provide a new therapeutic approach.
Who generates these activities? Our experimental work suggests that these activities are due to an excessive increase of chloride in striatal neuronal populations. This increase results in excitability of neurons that generate the giant currents. So the question is how to lower the chloride level? But it turns out that the diurétique- Bumétanide- known for its action on a major chloride input mechanisms in the kidney cells as in neurons completely block these giant currents (unpublished results). So, we undertook a pilot clinical trial of 4 PD patients with Professor P. Damier (Nantes) and obtained promising results (in progress).
With these observations, we created B&A Therapeutics with researchers and clinical experts of the understanding and treatment of Parkinson’s disease to understand the regulation of intracellular chloride and their effects on GABAergic signals, identify the neurons that generate these giant currents and undertake clinical trials to bring to market new agents to mitigate Parkinson’s disease.
