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.