Mass spectrometry is used to study the conformation of molecules and their interactions. From this analytical chemistry tool, which is over 100 years old, chemist Valérie Gabelica is making an innovative device for plunging into the heart of DNA and RNA. Work that has earned her the Research Prize.
A new lease of life for mass spectrometry
During her chemistry dissertation at the University of Liège in Belgium, Valérie Gabelica, who directs the European Institute of Chemistry and Biology (IECB) in Bordeaux, had only one idea in mind: to advance mass spectrometry, which analyzes the mass of molecules to deduce their composition. For what purpose? To study the structure of the nucleic acids, DNA and RNA, and their interactions with other molecules. In fact, together with her team created in 2013 through the Atip-Avenir program, the Inserm research director, who is also a European Research Council grant recipient, is behind some major advances. Her first feat was to demonstrate that the structure of nucleic acids differs depending on whether they are in a liquid or, as in a spectrometer, a gas phase. The structure deduced using spectrometry is therefore not entirely faithful to the structure the molecule had before entering the apparatus. « This challenging of our analyses, as well as those of other teams, generated a great deal of lively discussion when we presented our research, explains the chemist. Nevertheless, this phenomenon is now recognized and is taken into account by chemists when interpreting results. »
Phases and mirrors
Still on the subject of methodology, the team went on to focus on the measurement of chirality. A molecule is said to be « chiral » when it is not superimposable on its mirror image. Each version of the same molecule interacts differently. One can be therapeutic, the other toxic. Hence the pertinence of the method developed, which measures the chirality of each molecule in a mixture. Mass spectrometry identifies the compounds present, and a specific laser that probes the molecules directly in the spectrometer establishes under which version they appear. « Both technologies are common, but in order to combine them effectively we had to develop new concepts which included exploiting physical phenomena, » says Gabelica. A lot of work was involved! »
The harmful quadruple helix
As was the case with the latest research that she has recently published on the G‑quadruplex (G4) structures present on DNA. Basically, instead of the classic double helix, various DNA locations have a quadruple helix structure, which sometimes disrupts its replication and makes G4s potential targets for limiting the proliferation of cancer cells. The idea would be to use molecules that would stabilize the G4s of the tumor DNA. But this could be very complex. « After ten years of research, we have recently shown that when the most widely used stabilizing molecule in research binds to G4, it adopts a completely different structure, » explains Gabelica. So the biologists will have to study whether this remodeling influences the function of the G4. And take this phenomenon into account when designing other molecules. »
These latest findings illustrate the relevance of the analytical chemistry methods developed by the researcher for biologists, « among whom it took me a long time to popularize my research, » she acknowledges. A pitfall now overcome: in 2021 she took the helm of the IECB and now she has been awarded the Research Prize. « I’m very proud! This demonstrates the value that Inserm places on interdisciplinary research. It is also recognition that unconventional but creative themes are useful. »