Break­throughs in op­to­ge­net­ics

A new pro­ton pump dis­cov­ery in the field of op­to­ge­net­ics

The McGill Daily - - Con­tents - Naz Sutcuoglu Sci+tech Writer

Re­search in op­to­ge­net­ics is not of­ten men­tioned in ev­ery­day con­ver­sa­tion, but per­haps it should be. Op­to­ge­net­ics is a very new and fast-grow­ing area of re­search in the field of neu­ro­science which fo­cusses on the func­tions of cer­tain cells in the brain. In 2010, this area of re­search was named the “Method of the Year” by the Na­ture Meth­ods sci­en­tific jour­nal. Op­to­ge­net­ics is dif­fer­ent from other ar­eas of re­search be­cause it uses light to con­trol the neu­rons of in­ter­est in or­der to iden­tify their func­tions. Re­cently, sci­en­tists have found a new pro­ton ‘starter’ that can be used to con­trol mus­cles as well as neu­rons when us­ing op­to­ge­net­ics. This find­ing has the po­ten­tial to change lives in the near fu­ture, as well as to en­rich our un­der­stand­ing of the body in unimag­in­able ways.

How op­to­ge­net­ics works is quite unique. First, the de­sired neu­rons for re­search are ge­net­i­cally mod­i­fied to ex­press a light sen­si­tive pro­tein, opsin, which can take the form of an ion chan­nel, for ex­am­ple. Op­to­ge­net­ics works with Chan­nel­rhodopsins (Chrs), which are light­gated ion chan­nels. Light-gated ion chan­nels like Chrs are ac­ti­vated only when struck by a spe­cific fre­quency of light. When the cor­rect fre­quency is used to il­lu­mi­nate these neu­rons, it leads to an ion chan­nel open­ing. When these chan- nels are open, it al­lows the pas­sage of pos­i­tively-charged ions, which causes de­po­lar­i­sa­tion, also known as an ac­tion po­ten­tial. The abil­ity to con­trol spe­cific neu­rons by ma­nip­u­lat­ing their ac­ti­va­tion and de­ac­ti­va­tion us­ing light has led sci­en­tists to bet­ter un­der­stand mood dis­or­ders, ad­dic­tion, and even Parkin­son’s dis­ease. The key to un­der­stand­ing why and how such dis­or­ders and dis­eases oc­cur: to first find the path in which it takes place, and then what ex­actly goes wrong in that path.

The pro­ton ‘starter’ that was re­cently dis­cov­ered is known as nanohalosar­chaeon Nanos­alina (NSXER), and it be­longs to the class of pro­teins called xenorhodopsins. Xenorhodopsins func­tions have been bet­ter un­der­stood be­cause of this dis­cov­ery.

NSXER is a pow­er­ful pump which has been shown to in­duce ac­tion po­ten­tials in hip­pocam­pal neu­ronal cells to the per­fect fre­quency which opens those fre­quency gated chan­nels in rat brains. They have been char­ac­ter­ized as in­ward open­ing pumps that are an al­ter­na­tive to the Chrs that have been used in re­search un­til now. NSXER is very se­lec­tive and only pumps pro­tons into the cell, re­gard­less of the cells con­cen­tra­tion. Due to its se­lec­tiv­ity and unique fea­tures, it is con­sid­ered to be much more ad­van­ta­geous than Chrs. For in­stance, Nsx­ers se­lec­tiv­ity makes it safer to use dur­ing re­search, be­cause un­like Chrs, only one spe­cific pos­i­tive ion is be­ing trans­ported, low­er­ing the risk of pos­si­ble cel­lu­lar side ef­fects dur­ing re­search tri­als.

Op­to­ge­netic tech­niques have only been used in one hu­man clin­i­cal trial in 2016. A blind Texan wo­man un­der­went the first clin­i­cal trial us­ing op­to­ge­netic tech­niques. This has been the only hu­man trial done so far be­cause the meth­ods are quite in­va­sive. First, the brain needs to be ge­net­i­cally al­tered, and then a light de­liv­er­ing de­vice must be im­planted into the brain. How­ever, re­search in the field is rapid, and hopes of con­tin­u­ing hu­man clin­i­cal tri­als are high. The dis­cov­ery of NSXER brings re­searchers closer to the pos­si­bil­ity, which in turn brings them closer to ad­vance­ments in treat­ments for var­i­ous dis­eases and dis­or­ders re­searched in the field of neu­ro­science. This field of re­search may be the key we need to un­lock treat­ments for mil­lions of peo­ple around the world.

The pa­per on the find­ing of the NSXER pro­tein was pub­lished in Sci­ence Ad­vances by an in­ter­na­tional team of re­searchers from Moscow In­sti­tute of Physics and Tech­nol­ogy, Forschungszen­trum Jülich, and In­sti­tut de Bi­olo­gie Struc­turale. Vi­taly Shevchenko, the lead au­thor of the pa­per and a staff mem­ber at the MIPT Lab­o­ra­tory for Ad­vanced Stud­ies of Mem­brane Pro­teins stated, “So far we have all the nec­es­sary data on how the pro­tein func­tions. This will be­come the ba­sis of our fur­ther re­search aimed at op­ti­miz­ing and ad­just­ing the pro­tein pa­ram­e­ters to the needs of op­to­ge­net­ics.”

Re­cently, sci­en­tists have found a new pro­ton ‘starter’ that can be used to con­trol mus­cles as well as neu­rons. The abil­ity to con­trol spe­cific neu­rons by ma­nip­u­lat­ing their ac­ti­va­tion and de­ac­ti­va­tion us­ing light has al­lowed sci­en­tists to bet­ter un­der­stand mood dis­or­ders, ad­dic­tion, and even Parkin­son’s dis­ease.

Nishat Prova| Il­lus­tra­tor

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