Lluis M. Mir

Pulsed electric fields: models and applications

Lluis M. MIR
UMR 9018 METSY – Université Paris-Saclay, CNRS, Gustave Roussy
114 rue Edouard Vaillant, 94805 Villejuif, France

The use of electric pulses for therapeutic purposes was successfully developed by Lojze Vodovnik in the frame of the functional rehabilitation. When I met his team, namely Damjan Miklavcic, low amplitude DC fields were being tested as an antitumoral approach (1). However, the efficacy of electrochemotherapy (2) convinced both to use pulsed electric fields (PEFs), of high field amplitude, to produce the « electroporation » of the plasma membrane of the cells. This electroporation is a very interesting tool both in the biology laboratory as in medicine to treat cancer not only by electrochemotherapy (based on « reversible electroporation, a means to vectorize a non-permeant drug) (2) but also by irreversible electroporation (a non-thermal ablative procedure) (3,4). Electroporation can also be used to transfer nucleic acids not only in vitro but also in vivo directly in animals, for gene therapy or vaccination purposes (5,6).

In spite of the rapid development of the use of PEFs to modify the cells, the exact mechanisms of the “cell electroporation” remained unknown for a long time. Some investigators were even calling “electropermeabilisation” the cellular consequences of the exposure of the cells to the PEFs.  This lecture wil rapidly survey more than ten years of research dedicated to understand this phenomenon using technologies such as mass spectroscopy (7), RAMAN microspectroscopy (8,9), Coherent Anti-Stokes Raman Spectroscopy (10), and pulses of durations comprised between 10 ns and several ms. A comprehensive model resulted, in which electroporation and electropermeabilisation are two distinct steps of the consequence of exposing biological membranes to PEFs, that is, of cell electropulsation.

References

1. Miklavčič D, Serša G, Kryžanovski M, Novaković S, Bobanović F, Golouh R, Vodovnik L. Tumor treatment by direct electric current – tumor temperature and pH. Bioelectrochem. Bioenerg. 30: 209-220, 1993.
2. L.M. Mir, S. Orlowski, J. Belehradek Jr, C. Paoletti. Electrochemotherapy : Potentiation of antitumor effect of bleomycin by local electric pulses. Eur. J. of Cancer, 27, 68-72 (1991)
3. R.V. Davalos, L.M. Mir and B. Rubinsky. Tissue ablation with irreversible electroporation. Annals of Biomed. Engin. 33, 223-231, 2005.
4. M P Rols, C Delteil, M Golzio, P Dumond, S Cros, J Teissie. In vivo electrically mediated protein and gene transfer in murine melanoma. Nat Biotechnol. 1998 Feb;16(2):168-71.
5. L.M. Mir, M.F. Bureau, J. Gehl, R. Rangara, D. Rouy, J.-M. Caillaud, P. Delaere, D. Branellec, B. Schwartz and D. Scherman. High efficiency gene transfer into skeletal muscle mediated by electric pulses. Proceedings of the National Academy of Sciences USA, 96, 4262-4267, 1999.
6. B. Al-Sakere, C. Bernat, F. André, E. Connault, P. Opolon, R.V. Davalos, B. Rubinsky, L.M. Mir
   Tumor ablation with irreversible electroporation. PLoS One, 2 (11), e1135 – November 2007

7. M. Breton and L. M. Mir. Investigation of the Chemical Mechanisms Involved in the Electropulsation of Membranes at the Molecular Level. Bioelectrochemistry 119 (2018) 76-83;
8. A. Azan, V. Untereiner, C. Gobinet, G. D. Sockalingum, M. Breton, O. Piot and L. M. Mir. Demonstration of Protein Involvement in Living Cell Electropulsation using Confocal Raman Microspectroscopy. Scientific Reports 7. 297–306, 2017. doi:10.1038/srep40448.
9. A. Azan, V. Untereiner, L. Descamps, C. Merla, C. Gobinet, M. Breton, O. Piot and L. M. Mir

Comprehensive Characterization of the Interaction between Pulsed Electric Fields and Live Cells by Confocal Raman Microspectroscopy. Analytical Chemistry 89, 10790-10797, 2017.

10. C. Merla, M. Nardoni, M. Scherman, S. Petralito, L. Caramazza, F. Apollonio, M. Liberti, P. Paolicelli, B. Attal-Tretout, L.M. Mir. Changes in hydration of liposome membranes exposed to nanosecond electric pulses detected by wide-field Coherent anti-Stokes Raman microspectroscopy. Bioelectrochemistry. 2022 Oct;147:108218.

LLuis M. Mir

Mir did his graduate work at Ecole Normale Supérieure (Paris, France) and obtained his D.Sc. at Univ. of Toulouse, France, in 1983, in cell biology. Lluis M. Mir is DRCE emeritus at CNRS. In 2018, he received three Doctorates Honoris Causa (Univ. of Buenos Aires, U. Nacional Mayor San Marcos of Lima, and U. of Ljubljana). Currently, he is Member of the Standing Committee on Science Planning of the International Science Council. He is also fellow of the American Inst. for Medical and Biological Engineering and of the Int. Union of RadioScience (URSI), President of URSI-France and Past-President of the Int. Society of the Electroporation-Based Technologies and Treatments. He was visiting professor at the Univ. of Berkeley, Bielefeld and Jerusalem, served as Treasurer of the Bioelectrochemical Society and later as President of the European Bioelectromagnetics Association. Pr. Mir received the 2012 URSI-France  medal, the 2015 F. Reidy award in Bioelectrics, the 2017 URSI B. van der Pol Gold Medal and the 2021 G. Milazzo Prize in Bioelectrochemistry. Pr Mir published 250+ articles in peer reviewed journals and 26 chapters in books (H index 76). He pioneered the therapeutic uses of cell electroporation in Biology and Medicine. In particular, he developed the antitumor electrochemotherapy, from the inception to the first pre-clinical and clinical trials.