Scientific promise and social circulation of a “molecule of the year”: the case of Reactive Nitrogen
This PhD project proposes an interdisciplinary study of reactive nitrogen (RN), a family of chemical compounds whose uses, representations, and effects intersect scientific, industrial, environmental, health, and political fields. Positioned at the interface between biochemistry and the sociology of science, this work focuses on a central yet still little-discussed object in the social sciences: reactive nitrogen, and more specifically nitric oxide (NO), named molecule of the year by the journal Science in 1992. The discovery of the physiological role of NO led to the Nobel Prize in Medicine in 1998 and to the emergence of a new field of research supported by significant public and private funding, marked by the creation of new scientific societies, conferences and journals, and by the publication of more than 200,000 scientific articles in 30 years. At the crossroads of biomedical promises and scientific controversies, NO crystallizes a tension between, on the one hand, very strong therapeutic hopes and, on the other, major health consequences that are still poorly understood.
The project is structured around two main axes: Axis 1 – Promises and limits of scientific innovation. This axis aims to analyze the research trajectories surrounding NO since the 1990s: what promises were made, in what contexts, and why were some of them not fulfilled? The study will address both scientific and epistemological obstacles as well as institutional or political dimensions (disciplinary fragmentation, funding, research coordination, etc.). Axis 2 – Circulations, appropriations, and narratives. This axis follows NO and reactive nitrogen across different social arenas – laboratories, industry, regulation, politics, civil society – to understand how this biochemical entity is mobilized, defined, valorized, contested. Particular attention will be paid to the contradictory representations that coexist (beneficial molecule / toxic molecule), to problematic or incomplete uses, and to the effects of these circulations on public policy and social uses.
The approach adopted is multidisciplinary and will combine: i) an understanding of the biochemical nature of the object; ii) tools from the sociology of science, the history of technology, and studies of scientific controversies. The data to be collected will be: i) bibliometric data: use of databases such as OPENALEX / WOS; ii) documentary corpus: in-depth analysis of scientific archives, key publications, patents and institutional reports related to NO and RN, and media coverage of NO since the 1980s; iii) semi-structured interviews: a series of interviews will be conducted with various actors who have contributed to the study and use of NO, including: researchers who have worked on biomedical or ecological applications of NO; scientists who are members of the NO Society, a scholarly community dedicated to advancing knowledge on the NO molecule; industrial stakeholders involved in the technological valorization of reactive nitrogen compounds; policy makers and experts who have overseen regulation or public policies concerning NO and RN.
The expected results and contributions are as follows: From a scientific perspective, this research aims to establish the current state of social and scientific representations of reactive nitrogen / NO, to identify points of friction between academic spheres and public, commercial and political arenas, and to propose an analysis of the mechanisms of promise, valorization and misuse of knowledge. The thesis aims to enrich debates on the conditions of circulation of innovations and on the modalities of knowledge production in the life sciences. From a social and political perspective, it will contribute to a better understanding of the health and ecological issues linked to RN, and will formulate recommendations for decision-makers to better articulate expertise, responsibility and public policy.
From the perspective of supervision and research environment of the thesis... this project will be co-supervised by Jérôme Santolini (biochemist, Senior Researcher at CEA – Laboratory for Oxidative Stress and Detoxification), Michel Dubois (sociologist, Senior Researcher at CNRS) and Catherine Guaspare (sociologist, Research Engineer at CNRS). It will be conducted within two research units: CEA – DRF/Joliot: expertise in NO, reactive nitrogen and systemic redox approaches; GEMASS – CNRS-Sorbonne University: sociology of science and technology.
The doctoral student will benefit from a stimulating research environment, combining scientific investigation and critical reflexivity, with a strong interdisciplinary orientation and closely connected to public health and science communication issues
Accelerated high-resolution anatomical MRI at 11.7T using SPARKLING
Magnetic resonance Imaging (MRI) has become the reference neuroimaging technique for probing brain structure and function non-invasively. In particular, anatomical MRI is a gold standard for clinical imaging diagnosis and research, with T1-weighted imaging being the most commonly used sequence. However, the use of this imaging modality is limited by long acquisition times, especially for high resolution anatomical imaging. In this regard, non-Cartesian sampling can accelerate acquisitions through flexible sampling trajectories like SPARKLING, which can efficiently sample k-space and allow efficient and optimal iterative reconstructions with minimal degradation in image quality. In this PhD thesis, the SPARKLING framework which was originally developed for T2*-w imaging will be extended to MPRAGE T1-w imaging, with a goal to accelerate the acquisitions by a factor of 10-15 times, thereby allowing us to reach 1-mm isotropic acquisitions within a minute. Additionally, for extensions of anatomical imaging schemes involving redundant sampling at different inversion times (TI) like MP2RAGE, we propose a novel interleaved under-sampling acquisition and corresponding reconstruction scheme, which minimizes redundancy across different readouts, allowing us to maximally accelerate the acquisition process. In practice, this is achieved through 3D+time extension of the SPARKLING algorithm, that can be combined through the proposed 4D reconstruction scheme. Finally, the thesis will also focus on characterizing the noise profile in k-space for non-Cartesian acquisitions and its effect on the observed resolution in the reconstructed MR images. This will help us build SNR-optimized sampling trajectories, which will be validated against state-of-the-art and clinically utilized protocols (like MP2RAGE) at varying field strengths from 3T to 11.7T. Benchmarking of all the acquisition schemes will be performed through quantitative metrics and also qualitative radiological evaluations, through collaboration of radiologists at NeuroSpin and AP-HP Henri Mondor hospital.
Elucidating and exploiting the biosynthetic pathways of natural products to produce novel pharmacologically relevant molecules
Antimicrobial resistance (AMR) poses a significant global public health threat, necessitating the discovery of new antimicrobials. Natural products (NPs) are important reservoirs for such molecules. Among them, 2,5-diketopiperazines (DKPs) stand out due to their remarkable biological activities. DKP biosynthesis typically involves a core enzyme known as cyclodipeptide synthase (CDPS), which forms a cyclodipeptide scaffold, followed by one or more tailoring enzymes that introduce chemical modifications, leading to more complex DKPs. While the diversity of DKPs obtained is substantial, it remains limited since the initial cyclodipeptide scaffolds are predominantly composed of aromatic and hydrophobic amino acids.
Recently, novel core enzymes termed RCDPSs have been identified, showing no sequence homology to CDPSs. Notably, these RCDPSs utilize aminoacyl-tRNAs as substrates to synthesize cyclodipeptide scaffolds containing arginine.
This project proposes to investigate these RCDPSs, aiming to enable the biosynthesis of diverse DKPs containing arginine and other charged amino acids. The objectives are to establish the natural repertoire of cyclodipeptide scaffolds produced by these enzymes, understand the molecular basis of their substrate specificity, and ultimately perform enzymatic and metabolic engineering to generate a broader diversity of non-natural DKPs with charged amino acids. The project will be carried out using a range of biological (molecular biology, biochemistry, biophysics) and analytical chemistry (LC-MS) methods, with collaborations involving experts in structural biology and synthetic chemistry. If the project's progress allows, a collaboration will be established with an already identified platform to test the biological activity of the generated compounds.
Innovative pharmacological strategy to counter biohazard toxins
THESIS OBJECTIVE. Develop PROTAC molecules for proteasome-mediated degradation of toxins internalized in host cells, and propose drug candidates for in vivo studies at the end of the thesis.
BACKGROUND AND CHALLENGES. Plant and bacterial toxins are among the most toxic natural substances, and are responsible for fatal diseases such as botulism and tetanus. Once the toxin is internalized in the target cells, immunotherapy is ineffective, and there are no curative treatments for these biomolecules. One way of achieving a major breakthrough in the development of medical countermeasures would be to target the toxin directly into the cytoplasm of host cells using PROTAC molecules. PROTACs are heterobifunctional degraders that specifically eliminate targeted proteins by hijacking the cell's ubiquitin-proteasome system. This recent therapeutic strategy represents an attractive technology for new drug discovery.
METHODOLOGY. To carry out this project, the thesis student will carry out in silico screening campaigns to identify ligands for a toxin and improve their affinity. Key validation experiments will require recombinant production of a toxin fragment, and will be carried out in E. coli. From the most promising optimized ligands, targeted libraries of PROTAC molecules directed against the toxin will be synthesized in collaboration with a team of chemists. The student will evaluate the ability of these molecules to interact with and eliminate the internalized toxin in cultured cells using different approaches, in order to propose drug candidates for in vivo studies at the end of the thesis.
Optimizing cryogenic super-resolution microscopy for integrated structural biology
Super-resolution fluorescence microscopy (“nanoscopy”) enables biological imaging at the nanoscale. This technique has already revolutionized cell biology, and today it enters the field of structural biology. One major evolution concerns the development of nanoscopy at cryogenic temperature (“cryo-nanoscopy”). Cryo-nanoscopy offers several key advantages, notably the prospect of an extremely precise correlation with cryo-electron tomography (cryo-ET) data. However, cryo-nanoscopy has not provided super-resolved images of sufficiently high quality yet. This PhD project will focus on the optimization of cryo-nanoscopy using the Single Molecule Localization Microscopy (SMLM) method with fluorescent proteins (FPs) as markers. Our goal is to significantly improve the quality of achievable cryo-SMLM images by (i) engineering and better understanding the photophysical properties of various FPs at cryogenic temperature, (ii) modifying a cryo-SMLM microscope to collect better data and (iii) developing the nuclear pore complex (NPC) as a metrology tool to quantitatively evaluate cryo-SMLM performance. These developments will foster cryo- correlative (cryo-CLEM) studies linking cryo-nanoscopy and cryo-FIB-SEM-based electron tomography.
In vitro reconstitution of microtubule network polarization.
Microtubules, biological polymers present in all eukaryotic cells, serve as a support for intracellular transport via molecular motors, thus defining cellular polarity. Contrary to the dogma establishing the centrosome as the determinant of this polarity, research from the CytoMorpho Lab reveals that microtubules can self-organize without an organizing center. In vitro experiments have demonstrated that microtubules actively separate molecular motors of opposite polarities into distinct domains, creating a new mechanism of active phase separation. Such partitioning of space by microtubules and motors constitutes a new mechanism of morphogenesis. The doctoral project aims to encapsulate this system in lipid vesicles of controlled size to study how relative dimensions enable efficient polarization. This approach will require the development of a microfluidic device and optimization of biochemical conditions for anchoring motors in the lipid bilayer. The perspectives include the creation of "artificial cells" capable of polarization and the reevaluation of cellular polarization models, particularly for T lymphocytes and other differentiated cells.
The solid-state systems, presently considered for quantum computation, are built from localized two-level systems, prime examples are superconducting qubits or semiconducting
quantum dots. Due to the fact that they are localized, they require a fixed amount of hardware per qubit.
Propagating or “flying” qubits have distinct advantages with respect to localised ones: the hardware footprint depends only on the gates and the qubits themselves (photons) can be created on demand making these systems easily scalable. A qubit that would combine the advantages of localised two-level systems and flying qubits would provide a paradigm shift in quantum technology. In the long term, the availability of these objects would unlock the possibility to build a universal quantum computer that combines a small, fixed hardware footprint and an arbitrarily large number of qubits with long-range interactions. A promising approach in this direction is to use electrons rather than
photons to realise such flying qubits. The advantage of electronic excitations is the Coulomb interaction, which allows the implementation of a two-qubit gate.
The aim of the present Phd will be the development of the first quantum-nanoelectronic platform for the creation, manipulation and detection of flying electrons on time scales down to the picosecond and to exploit them for quantum technologies.
Measuring quantum decoherence and entanglement in attosecond photoemission
The PhD project is centered on the advanced study of attosecond photoemission dynamics. The objective is to access in real time decoherence processes induced, e.g., by electron-ion quantum entanglement. To that aim, the young researcher will develop attosecond spectroscopy techniques making use of a new high repetition rate Ytterbium laser.
Detailed summary :
In recent years, there has been spectacular progress in the generation of attosecond (1 as=10-18 s) pulses, awarded the 2023 Nobel Prize [1]. These ultrashort pulses are generated from the strong nonlinear interaction of short intense laser pulses with gas jets [2]. They have opened new prospects for the exploration of matter at the electron intrinsic timescale. Attosecond spectroscopy allows studying in real time the quantum process of photoemission and shooting the 3D movie of the electron wavepacket ejection [3, 4]. However, these studies were confined to fully coherent dynamics by the lack of experimental and theoretical tools to deal with decoherence and quantum entanglement. Recently, two techniques have been proposed to perform a quantum tomography of the photoelectron in its final asymptotic state [5, 6].
The objective of the PhD project is to develop attosecond spectroscopy to access the full time evolution of decoherence and entanglement during the photoemission process. Quantum tomographic techniques will be implemented on the ATTOLab laser platform (https://iramis.cea.fr/en/lidyl/atto/attolab-platform/) using a new Ytterbium laser source. This novel laser technology is emerging, with stability 5 times higher and repetition rate 10 times higher than the current Titanium:Sapphire technology. These new capabilities represent a breakthrough for the field and allow, e.g., charged particle coincidence techniques, to study the dynamics of photoemission and quantum entanglement with unprecedented precision.
This PhD project is performed in the frame of a recently funded European Network QU-ATTO (https://quatto.eu/), providing an advanced training to 15 young researchers, and opening many opportunities of joint work with European laboratories. In particular, strong collaborations are already ongoing with the groups of Prof. Anne L’Huillier in Lund, and Prof. Giuseppe Sansone in Freiburg. Due to the Mobility Rule, candidates must not have resided (work, studies) in France for more than 12 months since August 2022.
The student will receive solid training in ultrafast optics, atomic and molecular physics, attosecond science, quantum optics, and will acquire a broad mastery of XUV and charged-particle spectroscopy techniques.
References :
[1] https://www.nobelprize.org/prizes/physics/2023/summary/
[2] Y. Mairesse, et al., Science 302, 1540 (2003)
[3] V. Gruson, et al., Science 354, 734 (2016)
[4] A. Autuori, et al., Science Advances 8, eabl7594 (2022)
[5] C. Bourassin-Bouchet, et al., Phys. Rev. X 10, 031048 (2020)
[6] H. Laurell, et al., Nature Photonics, https://doi.org/10.1038/s41566-024-01607-8 (2025)
Development and study of laminated composite material with carbon nanotubes functionalisation dedicated to launcher linerless cryogenic tank
The use of composite materials in the space field has led to great weight improvements. To continue to achieve significant weight gain, composite cryogenic tank is the next technological application to reach by replacing the current metal alloy cryogenic propellant tanks. Lighter reinforced organic matrix composite materials (that are at least as efficient from a mechanical, thermal, chemical and ignition resistance point of view) are a realistic target to be reached that has been explored in recent years. Many research approaches tend to answer to this technological lock, but the potentialities of Carbon NanoTubes (CNTs) in terms of mechanical and physical properties, need to be explored deeper.
A first phase to assess the interest of CNTs for space applications (collaboration CNES/CEA/I2M/CMP Composite) was carried out to associate CNTs with a cyanate ester matrix in layered composite materials through three processes: (i) transfer of aligned CNTs mats by hot pressing (ii) dispersion of entangled CNTs mixed with resin, or (iii) growth of nanotubes aligned directly on the dry ply. Knowing mechanical and thermal loads, the aim is to demonstrate the efficiency of CNTs and influence of their characteristics with regard to damage tolerance of the material and consist in delaying the cracking process of the composite nearby the CNT layer and thus blocking the percolation of the cracking network which leads to the loss of tightness. For the preferred development process identified, the aim of this doctoral work is now to consolidate the material functionalisation with CNTs (shape, density, etc.) and the understanding of the mechanical behaviour (at room temperature and at low temperature) for the development of the layered material integrating CNTs.
Knowing the potential final application as cryogenic tank or for the improvement of structural materials sustainability in dual application, relevant tests will be performed to demonstrate the impact in terms of damage development and tightness in comparison with the same material without CNTs.
Alternatives to perfluorinated compounds for water-repellent and oil-repellent treatments of textiles used for NRBC personal body protection
Finding alternatives to fluorinated compounds (PFAS) involves very diverse application areas. Among them, the treatment of technical textiles to make them water- and oil-repellent is a major challenge for manufacturing protective clothing against both aqueous and oily contaminants. Our laboratory is developing such alternatives by covalently grafting molecules onto fibers selected from those already used for technical textiles. The thesis will focus on experimental work with two components. The first component will consist of improving and qualifying, at a semi-industrial level, the water- and oil-repellent properties already obtained and qualified according to current standards (water and oil droplet sliding, slow impregnation of oil droplets) using our nanometric chemical coatings. The second component will be dedicated to optimizing the weave structure, in conjunction with the chemical treatment, to determine the optimal weave based on the desired properties. The work will be carried out in close contact with a technical textile manufacturer and with ENSAIT in Roubaix.