CV Science

Nicolas Gambardella PhD Molecular and Cellular Pharmacology

Course and current status

Education and training

• 2013: HDR Habilitation to supervise research (University Bordeaux II)
• 1998: PhD Molecular and Cellular Pharmacology (University Paris VI)
• 1993: MSc Evolution, biophysics, neuroendocrinology (École Normale Supérieure, Paris)
• 1991: BSc Cellular Biology and Physiology (University Paris VI)
• 1988: Scientific Baccalaureate (Prytanée National Militaire, La Flèche, France)

Position and employment

• 2023-present: Senior scientist (Directeur de recherche), CNRS, European Genomic Institute for Diabetes; Lille, FR.
• 2019-2023: Consultant in data analysis, modelling, science copywriting, and language translation, aSciStance Limited (founder and director); Cambridge, UK.
• 2012-2018: Senior Group leader, Babraham Institute; Babraham, Cambridge, UK.
• 2014-2015: Chief Data Officer, Curie Institute; Paris, FR.
• 2003-2012: Group leader, EMBL-EBI; Hinxton, Cambridge, UK.
• 2001-2003: Researcher (CR), CNRS URA 2182, Récepteurs et Cognition; Institut Pasteur, Paris, FR.
• 1999-2001: Post-doctoral fellow, Computational Cell Biology, University of Cambridge, Cambridge, UK.
• 1992-1999: Undergraduate, PhD student, and post-doctoral fellow, CNRS URA D1284, Neurobiologie Moléculaire; Institut Pasteur, 25, rue du Dr ROUX, 75724 Paris cedex 15.
• 1991: Undergraduate student, INSERM 153, Service of Développement, Pathologie, Régénération du système neuromusculaire; 17, rue du fer à moulin, 75005 Paris.

Scientific summary

Over 200 publications including 142 peer-reviewed, >29000 citations, H-index=75

nAChR sequence and structure

My PhD studies in the group of Jean-Pierre Changeux at the Pasteur Institute focused on neuronal nicotinic receptors, a model of neurotransmitter receptors, responsible among other things of tobacco addition. When I started in 1992, a few subunits had been sequenced but no systematic bioinformatics analysis had been performed. I, therefore, collected them in a public database (Ligand-Gated Ion Channel Database), reconstructed their evolution, predicted their structure. I showed that neuronal nicotinic receptors were made of three types of subunits, and not two as previously thought. I predicted the receptor as being mostly made of β-sheets and proposed a fold and a quaternary assembly. Based on the structure of a soluble homologous protein, I modelled the 3D structure of the nAChR and discovered allosteric calcium sites.

• Le Novère N, Changeux JP (1995) Molecular evolution of the nicotinic acetylcholine receptor: an example of multigene family in excitable cells. J Mol Evol 40: 155-172. doi:10.1007/BF00167110 [592 citations]
• Le Novère N, Corringer PJ, Changeux JP(1999) Improved secondary structure predictions for a nicotinic receptor subunit. Incorporation of solvent accessibility and experimental data into a 2D representation. Biophys J, 76: 2329-2345. doi:10.1016/S0006-3495(99)77390-X [122 citations]
• Corringer PJ, Le Novère N, Changeux JP (2000) Nicotinic receptors at the amino acid level. Ann Rev Pharm Tox 40: 431-458 doi:10.1146/annurev.pharmtox.40.1.431 [1101 citations]

Distribution and function of neuronal nAChR

 In parallel with my bioinformatics analysis, I systematically mapped the distribution of nAChR subunits in the nervous system of rodents and primates, in adults and during development. I found that the subunit α6 was specifically expressed in the brain areas linked to the reward-related responses to nicotine. Inhibition of its expression confirmed this role. Since then, α6 has been shown one of the key components of the nAChRs responsible for tobacco addiction.

• Zoli M, Le Novère N, Hill JA, Changeux JP (1995). Developmental regulation of nicotinic ACh receptor subunit mRNAs in the rat central and peripheral nervous systems. J Neurosci, 15: 1912-1939. http://www.jneurosci.org/content/15/3/1912 [400 citations]
• Le Novère N, Zoli M, Changeux JP (1996). Neuronal nicotinic receptor α6 subunit mRNA is selectively concentrated in catecholaminergic nuclei of the rat brain. Eur J Neurosci, 8: 2428-2439. doi:10.1111/j.1460-9568.1996.tb01206.x [476 citations]
• Le Novère N, Zoli M, Léna C, Ferrari R, Picciotto MR, Merlo-Pich E, Changeux JP (1999) Involvement of α6 nicotinic receptor subunit in nicotine-elicited locomotion, demonstrated by in vivo antisense oligonucleotide infusion. NeuroReport, 10(12): 2497-2501. http://lenoverelab.org/perso/lenov/PUBLIS/Lenov1999c.pdf [114 citations]
• Le Novère N, Corringer PJ, Changeux JP (2002) The diversity of subunit composition in nAChRs: evolutionary origins, physiologic and pharacologic consequences. J Neurobiol, 53(4): 447-456. doi:10.1002/neu.10153 [508 citations]

Bacterial Chemotaxis

During my post-doctoral research in the group of Dr Dennis Bray at the University of Cambridge, I focused my research on a different signalling system, regulating bacterial chemotaxis. The central object of our studies was the large cooperative protein assemblies responsible for the observed ultrasensitivity of response. Based on existing protein structures, mutational analysis, and functional constraints, we developed an accurate structural model of the receptor assembly. The basic hexagonal three-layered lattice structure was confirmed in 2008 by electron microscopy. On the side of the flagellar response, we proposed a switch-like behaviour of the motor based on conformational spread which was experimentally validated in 2010.

• Shimizu TS, Le Novère N, Levin MD, Beavil AJ, Sutton BJ, Bray D (2000) Molecular model of a lattice of signalling proteins involved in bacterial chemotaxis. Nat Cell Biol, 2: 792-796. doi:10.1038/35041030 [264 citations]
• Le Novère N, Shimizu TS (2001) StochSim: Modelling of stochastic biomolecular processes. Bioinformatics, 17: 575-576. doi:10.1093/bioinformatics/17.6.575 [283 citations]
• Duke TAJ, Le Novère N, Bray D (2001) Conformational spread in a ring of proteins: a stochastic approach to allostery. J Mol Biol, 308:541-553. doi:10.1006/jmbi.2001.4610 [267 citations]

Allosteric calcium sensors and synaptic plasticity

For the last 30 years or so, one of the main theories to explain the bidirectional plasticity of excitatory synapses relies on differential activation by calcium signals of kinase or phosphatase. However, using usual thermodynamic models of calmodulin, based on induced-fit, could not explain that observation. We developed a series of allosteric models of calmodulin, Calcineurin and Ca/Calmodulin Kinase II. We could explain why low calcium activates calcineurin while high calcium activates Ca/Calmodulin Kinase II, and show that the frequency dependence of plasticity is not fixed but depends on the regime of stimulation. Kinetic models unravelled unexpected allosteric stabilization of calmodulin targets.

• Stefan MI, Edelstein SJ, Le Novère N (2008) An allosteric model of calmodulin explains differential activation of PP2B and CaMKII. PNAS, 105: 10768-10773. doi:10.1073/pnas.0804672105 [102 citations]   
• Li L, Stefan MI, Le Novère N  (2012) Calcium input frequency, duration and amplitude differentially modulate the relative activation of calcineurin and CaMKII. PLoS ONE, 7(9): e43810. doi:10.1371/journal.pone.0043810 [134 citations]   
• Lai M, Brun D, Edelstein SJ, Le Novère N (2015) Modulation of calmodulin lobes by different targets: an allosteric model with hemiconcerted conformational transitions. PLoS Comput Biol  10(1):e0116616. doi:10.1371/journal.pcbi.1004063 [40 citations]

Resources to share and re-use mathematical models

I became involved in the development of the Systems Biology Markup Language (SBML) from its creation and was an editor for the best part of a decade. After SBML was created, the number of models available increased rapidly. In order to facilitate their retrieval and re-use, we created BioModels, a repository of curated models. BioModels is now the largest and most used database of computational models in systems biology. Realized that encoding the structure of the model was insufficient to allow its efficient re-use, we coordinated the development of community guidelines to encode, curate, annotate and share models such as MIRIAM, and the associated tools, including ontologies. This was completed with the MIASE guidelines and the SED-ML format allowing the description of simulation and analysis steps. We also developed the Systems Biology Graphical Notation (SBGN), the first consistent and well supported graphical standard in biochemistry.

• Le Novère N, [+15 authors] (2005) Minimum Information Requested In the Annotation of biochemical Models (MIRIAM) Nat Biotechnol, 23: 1509-1515. doi:10.1038/nbt1156 [694 citations]
• Le Novère N, [+12 authors] (2006) BioModels Database: A Free, Centralized Database of Curated, Published, Quantitative Kinetic Models of Biochemical and Cellular Systems. Nucleic Acids Res, 34: D689-D691. doi:10.1093/nar/gkj092 [978 citations]
• Le Novère N, [+34 authors] (2009) The Systems Biology Graphical Notation. Nat Biotechnol, 27: 735-741. doi:10.1038/nbt.1558 [1049 citations]\
• Courtot M, [25 other authors], Le Novère N. (2011) Controlled vocabularies and semantics in Systems Biology. Mol Syst Biol, 7: 543. doi:10.1038/msb.2011.77 [335 citations]
• Hucka M, [+39 authors] (2003) The Systems Biology Markup Language (SBML): A Medium for Representation and Exchange of Biochemical Network Models. Bioinformatics, 19: 524-531. doi:10.1093/bioinformatics/btg015 [3804 citations]

RNA-seq analyses

 
Over the last decade, I introduced RNA-seq and network inference in my group to diversify the approaches used to study our and our collaborators model systems. While the resulting publications do not form a consistent story as the examples above, the few listed below demonstrate the breadth of the questions I studied.

• Kiselev VY [+4 authors], Le Novère N, Stephens LR (2015) Perturbations of PIP3 signalling trigger a global remodelling of mRNA landscape and reveal a transcriptional feedback loop. Nucleic Acids Res (2015) 43 (20): 9663-9679. doi:10.1093/nar/gkv1015 [23 citations]
• Díaz-Mũnoz MD, Kiselev VY, Le Novère N, [3 authors] (2017) Tia1 dependent
  regulation of mRNA subcellular location and translation controls p53 expression in B cells. Nat Comm 8:530. doi:10.1038/s41467-017-00454-2 [63 citations]
• Hastings J, [6 authors],  Le Novère N, Casanueva O (2019) Multi-omics and genome-scale modeling reveal a metabolic shift during C. elegans aging.
  Front Mol Biosci (2019) 6: 2. doi:10.3389/fmolb.2019.00002 [58 citations]
• Bargher J, [+6 Authors], Le Novère N, [+12 authors] (2019) Human embryonic stem cell-derived epicardial cells augment cardiomyocyte-driven heart regeneration. Nat Biotechnol, 37(8):895-906. doi:10.1038/s41587-019-0197-9 [162 citations]
• Gambardella L, [+9 authors], Gambardella Le Novère N, Sinha S (2019) BNC1 regulates cell heterogeneity in human pluripotent stem cell derived-epicardium. Development, 146:dev174441. doi:10.1242/dev.174441 [34 citations]
• Montalban E, [+22 authors], Gambardella N, [+2 authors] (2022) Translational profiling of mouse dopaminoceptive neurons reveals a role of PGE2 in dorsal striatum. Mol Psy, 27:2068–2079.doi:10.1038/s41380-022-01439-4. [13 citations]
• Montalban E, [+12 authors], Gambardella N, [+2 authors] (2023) Operant training for highly palatable food alters translating mRNA in nucleus accumbens D2 neurons and reveals a modulatory role of Ncdn. Biol Psy 95(10): 926-937. doi:10.1101/2023.03.07.531496 [1 citation]