Researchers at the Turku Centre for Biotechnology have invented new tools to decode and control signalling circuits in living cells with flashes of light. In principle, any cellular circuit can now be targeted with their method. Using this approach, they discovered that major biological signalling circuits can be made to resonate when driven at their resonant frequency.

Resonance is a familiar concept in music, physics and engineering and underlies technical approaches in chemistry, biology and medicine.
– Our discovery that signalling circuits of mammalian cells can made to resonate, is new and is likely to have relevance to disease. With this information we may control, when the signalling pathway is on or off, senior researcher Michael Courtney from Turku Centre for Biotechnology says.

The team developed optogenetic inhibitors of protein kinases such as JNK, a central regulator of cell function.
– JNK protein in the cell cytoplasm was not thought to regulate gene expression in the nucleus and continuous inhibition in the cytoplasm is ineffective. However, the team found that delivering a specific frequency of inhibition pulses to JNK in the cytoplasm drove inhibition of gene expression in the nucleus. This indicates that cell signalling circuits can be controlled in previously unforeseen ways once the appropriate time-code has been identified, Courtney says.

He explains that not only might cell circuit resonance play an unexpected role in degenerative disease processes, but it could even guide the discovery of new therapeutic approaches. Interestingly, the only previous report on cell circuit resonance in the scientific literature showed it can be used to prevent microbial cells from growing. The new finding of similar behaviour in mammals suggests it could potentially be used to stop cancer cells growing.

– Currently, the development of resistance to new drugs is a major problem in cancer, as new drugs cost billions of dollars to develop and approve and yet they can rapidly become ineffective in patients. With new research, we can perhaps consider to change the frequency of inhibition instead of using the same drug continuously, and in this way, achieve a better outcome, Courtney says.

The Turku team’s newly discovered phenomenon of circuit resonance in mammalian cells might offer a way to avoid or work around drug resistance. The researchers have now assembled a research consortium which has applied for funding to begin the evaluation of this idea.
The team started developing the light-regulated tools while at the University of Eastern Finland funded primarily by the Academy of Finland Photonics programme. The mammalian circuit resonance was discovered and characterised by the team after moving to the University of Turku, with support from the Turku Bioimaging Screening Unit and grants from the National Cancer Institute in US, the EU-Marie Sk?odowska Curie programme and Finnish foundations including the Magnus Ehrnrooth, Alfred Kordelin, Instrumentarium and Orion Foundations.

This work was published in the journal Nature Communications on the 12th of May 2017.
Original publication: Melero-Fernandez de Mera RM¹, Li LL¹, Popinigis A, Cisek K, Tuittila M, Yadav L, Serva A, Courtney MJ (2017) A simple optogenetic MAPK inhibitor design reveals resonance between transcription-regulating circuitry and temporally-encoded inputs. ¹equal contribution. Nat. Commun. 8, 15017 doi: 10.1038/ncomms15017.
Read the article: https://www.nature.com/articles/ncomms15017

More information: Senior Researcher Michael Courtney, University of Turku, Turku Centre for Biotechnology, tel. +358 (0)504649827 , e-mail miccou@utu.fi