PhD in chemistry (M/F) – Analytical developments in ultra-sensitive NMR approaches for metabolomics

Nuclear Magnetic Resonance (NMR) spectroscopy is a method of choice for the quantitative analysis of complex mixtures such as biological samples typically encountered in metabolomics. However, its sensitivity remains limited. In this context, the CEISAM laboratory has recently acquired a dynamic nuclear polarization (DNP) instrument—unique in Europe—that, when coupled to an NMR spectrometer, enhances the sensitivity of 13C NMR by several orders of magnitude [1]. This equipment will be upgraded in 2026 with a rapid-transfer system between the polarizer and the NMR spectrometer, enabling ultra-sensitive 1H acquisitions. The DNP approach relies on preparing a hyperpolarized state through electron–nuclei polarization transfer by microwave irradiation of the sample at low temperature. Once this state is reached, the sample is rapidly transferred to the NMR spectrometer, allowing ultra-sensitive detection within a limited time window. We recently demonstrated, for the first time worldwide, that this method can be applied to 13C NMR metabolomics at natural abundance [2]. Beyond this proof of concept, substantial analytical developments are still required to broaden the applicability of this approach in metabolomics. Dedicated acquisition and data-processing tools suitable for complex mixtures are essential, such as fast 2D NMR [3] or the simultaneous detection of NMR responses originating from multiple nuclei [4]. Many analytical challenges remain, particularly concerning the quantification and identification of NMR signals obtained using these methods.

The aim of this PhD project is to optimize a complete DNP-hyperpolarized NMR workflow for the analysis of biological samples (including clinical samples such as urine or blood plasma) and to evaluate its potential for metabolomics. This work lies at the interface between NMR spectroscopy and analytical chemistry, requiring strong involvement both in understanding and developing hyperpolarized NMR approaches and in mastering the entire metabolomics workflow—from sample preparation to statistical data analysis.

References

1.         Plainchont, B., et al., Dynamic Nuclear Polarization Opens New Perspectives for NMR Spectroscopy in Analytical Chemistry. Analytical Chemistry, 2018. 90(6): p. 3639-3650.

2.         Dey, A.., et al., Hyperpolarized 13C NMR Metabolomics of Urine Samples at Natural Abundance Applied to Chronic Kidney Disease. J. Am. Chem. Soc., 2025. 147: p. 644-650

3.         Giraudeau, P. and L. Frydman, Ultrafast 2D NMR: An Emerging Tool in Analytical Spectroscopy. Annu. Rev. Anal. Chem., 2014. 7: p. 129-161.

4.         Dey, A., et al. Hyperpolarized 1H and 13C NMR Spectroscopy in a Single Experiment for Metabolomics Anal. Chem., 2023, 95, p. 16861-16867

The PhD candidate will be responsible for:

• Optimizing sample preparation and hyperpolarized 1D and 2D NMR analysis conditions for complex mixture analysis;
• Assessing the potential and limitations of this approach for the identification and quantification of biological samples;
• Analyzing series of biological samples (including clinical samples provided by collaborators at INSERM and the University of Tours);
• Processing the resulting data using statistical approaches;
• Interpreting the results with a critical analytical chemistry perspective and comparing them with those obtained using standard methods.

Candidates should have a background in chemistry (preferably physical or analytical chemistry) and an interest in developing analytical methods and applying them to metabolomics. Strong rigor in analytical chemistry and a genuine interest in NMR methodology are essential. Due to the highly collaborative nature of the project, excellent communication skills in both French and English are required.

The PhD candidate will also be expected to share knowledge with other students (Master’s and PhD) and present their work at international conferences and project meetings. Opportunities for teaching assignments will be offered, and the supervising team will place high priority on the candidate’s training.