Remote regulation of glucose homeostasis in mice using genetically encoded nanoparticles
Authors: Jonathan S Dordick
Jeremy Sauer
Ravi S Kane
Jeffrey M Friedman
Sarah A Stanley
Journal: Nature Medicine (2015)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: gene expression; cellular activity; genetically encoded system; remote regulation; radio waves
Affiliations: Laboratory of Molecular Genetics, Rockefeller University, New York, New York, USA., Department of Chemical and Biological Engineering, Department of Biology, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York, USA., Howard Hughes Medical Institute, New York, New York, USA.

Abstract:  Means for temporally regulating gene expression and cellular activity are invaluable for elucidating underlying physiological processes and would have therapeutic implications. Here we report the development of a genetically encoded system for remote regulation of gene expression by low-frequency radio waves (RFs) or a magnetic field. Iron oxide nanoparticles are synthesized intracellularly as a GFP-tagged ferritin heavy and light chain fusion. The ferritin nanoparticles associate with a camelid anti-GFP-transient receptor potential vanilloid 1 fusion protein, αGFP-TRPV1, and can transduce noninvasive RF or magnetic fields into channel activation, also showing that TRPV1 can transduce a mechanical stimulus. This, in turn, initiates calcium-dependent transgene expression. In mice with stem cell or viral expression of these genetically encoded components, remote stimulation of insulin transgene expression with RF or a magnet lowers blood glucose. This robust, repeatable method for remote regulation in vivo may ultimately have applications in basic science, technology and therapeutics. 

Retracted: No

PubPeer comments:
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 ![file] Figure 1c and d Corresponding description in the results section of the manuscript: *The N-terminalu2013modified TRPV1 was able to respond to the TRP agonist 2APB, as 2APB significantly increased intracellular calcium in HEK cells transfected with u03b1GFP-TRPV1 (2.0-fold versus 0.85-fold change in Fluo-4 fluorescence in untransfected cells (Fig. 1c)). Finally, exposing HEK cells expressing u03b1GFP-TRPV1 GFP-ferritin to radio waves (465 kHz) significantly increased intracellular calcium compared with what was seen in nontransfected controls (2.9-fold versus 0.8-fold change in Fluo-4 fluorescence, Fig. 1d).* There is a very inappropriate experimental setting. The authors claimed that they recorded calcium influx using the Fluo-4 dye in HEK cells expressing u03b1GFP-TRPV1 GFP-ferritin, however the dye is a green calcium indicator overlapping EGFP, FITC or Alex 488 spectra. In this context, if the authors decided to use the EGFP fused to a chimeric ferritin, using a green indicator for calcium influx should have been  avoided . The difficulty of such experiment is also discussed in https: www.researchgate.net post Are_GFP_and_calcium_indicator_Fluo-4_spectra_discernible , 
 #1 The response in the Markus Meister article matches what I believe, the force generated by the proposed mechanism seems orders of magnitude off. The temperature difference between the iron atoms in proteins and the surrounding water molecules are extremely small. If the experimental results are true, it may as well be a temperature induced change in ion channel dynamics due to RF-heating, rather than a RF induced gating mechanism. , 
 See the paper below: https: www.biorxiv.org content 10.1101 737254v1 The observed phenomena in this Nat Med paper havenu2019t been extensively reproduced. ,