DS03 - Stimuler le renouveau industriel

Modulated Super-resolved Microscopy : nanometric molecular organization of cells – MSM

Submission summary

Super-resolution optical microscopies, which were awarded the Nobel Prize 2014, represent a true revolution in biology. Their ultimate sensitivities, allowing the tracking of unique molecules, as well as their nanometric resolution, unveil, for the first time, the organization and intracellular mechanisms at the molecular level.
The objective of this project is to introduce a new concept in super-resolution optical microscopy. Modulated Super-resolution Microscopy (MSM) represents a radically new approach to encode information from individual emitters. This modulated information is extracted by an original multiplexed homodyne detection taking full advantage of the specificities of super-resolution microscopy, in particular the sparse distribution of the emitters. The MSM thus brings all the advantages of homodyne detection in super-resolution microscopy. These advantages are especially relevant in particular in terms of insensitivity to light fluctuations and gain in signal to noise ratio. Moreover, the concept being generic, it is declined in the project to push the limits of current techniques, in particular in terms of resolution or dynamics, and to realize new functionalities such as 3D orientational microscopy at the individual molecule scale.
In MSM, the spatial modulation of the light excitation makes it possible to code the transverse position of the emitters. The developed models allow us to expect a localization gain of one order of magnitude compared to the standard techniques (centroids). The preliminary experiments are extremely encouraging, already showing record localization at the nanometer.
Axial resolution, giving access to 3D imaging, is still a crucial issue in super-resolution microscopy requiring complex additional techniques. This project proposes an original solution in MSM to code this information based on the use of tilted interference fringes. This modality can be implemented simply on a standard 2D super-resolution microscope. It should offer 3D iso-resolution without altering the lateral resolution. Moreover, homodyne detection is not very sensitive to aberrations induced by the propagation in the biological medium and background noise, the capture depth of this technique should thus be much greater than that associated to standard techniques.
Accessing the local environment or the orientation at the scale of an individual molecule within a cell would represent a true breakthrough in biology by allowing one to go beyond statistical averaged measurements. Despite the efforts of many research teams in this field, this remains very difficult, if not impossible. The MSM provides access to this information by encoding the polarization or fluorescence lifetime. Compatible with standard super-resolution microscopy, without degrading their performance, this coding uses the whole set of photons emitted to extract information from a single molecule. Inter-molecular variability becomes a new and extraordinary source of information for the understanding of cellular mechanisms.
This project also wants to demonstrate the performance and interest of the MSM by answering major biological questions. Microtubules represent a reference object for super-resolution microscopy, but beyond this, it has recently become apparent that the fine nanoscale architecture of the microtubule cytoskeleton partly determines its dynamics and hence impacts cellular activity, polarization and migration, which are altered in cancer cells and are the target of treatment with anti-mitotic agents. Different implementations of the MSM will make it possible to reveal them in this project.
The technology of this project is patented and valorization will be a constant concern of the consortium.

Project coordination

Sandrine Lévêque-Fort (Institut des Sciences Moléculaires d'Orsay)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.


ISMO Institut des Sciences Moléculaires d'Orsay
Institut Langevin Institut Langevin Ondes et Images

Help of the ANR 485,653 euros
Beginning and duration of the scientific project: September 2017 - 36 Months

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