ETERNAlly Evolving: Ideas on possible future directions for labs/puzzles.

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 Over 400 Labs or other projects have been the conducted in Eterna.
     In these labs :

The sequences which allow for specific RNA structures have been elucidated. 
RNA folding strategies of Bots have been bested by the strategies of Eterna players.
Puzzle Results in silico have been compared with results in vitro.
The effects of symmetry in structure (and in sequence) on RNA design have been studied.
RNA switches have been designed with up to 4 different states depending on conditions.
RNA sensors have been constructed which can detect the presence of other molecules.
Labs have worked to create diagnostic tools for medicine (lives may be saved).
And Results of many of the labs have been published.    

     And THIS is only the beginning

 Far more than folding into intricate shapes and binding to specific ligands, RNAs catalyze some of the most essential enzymatic processes within living organisms (think splicing reactions and protein translation), as well as direct a number of enzymatic processes which are carried out by proteins. 

       What I hope to start in this thread is a discussion on how to test for and create RNA function via Eterna.

   Consider a puzzle where instead of a specific shape being the target for solving the puzzle, the target was rather a specific catalytic activity (such as catalyzing a cleavage reaction), or the target (conversely) could be for RNA to be able to be the substrate for a specific catalytic activity (such as site-specific deamination of A or U).
     
     I hope to hear your thoughts on this; let me know what you think! :-D  
    

Also, thank you to LFP6 and rhiju for encouraging me to post this idea on the Forum. 
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cynwulf28

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  • that you may be pondering what I am pondering; are you?

Posted 3 years ago

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rhiju, Researcher

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Nice post! The dev team has been thinking about next steps towards building really amazing functions -- and we have been sending out proposals to join Eterna with other labs to do some cool things:

+ Create the molecules needed to diagnose diseases like tuberculosis with cheap 'paper devices', like pregnancy kits.

+  Reengineer ribosomes (the machines that make all proteins in our cells as well as blockbuster therapeutics) to make other polymers and fabrics. This required understanding RNA catalysis, an aspect of function that I can tell you're excited about!.

+ Create CRISPRi and CRISPRa RNA-guided complexes to learn how to rationally adjust how human cells behave, hopefully leading to principles to fight cardivascular disease or cancer.

We're seeing some real movement on the openTB project, as you know from looking at the labs. Prof. Purvesh Khatri also gave an amazing talk at Eternacon on this [@LFP6 can you get the video up?]. He highlighted how if Eterna succeeds with OpenTB, we can start to create RNA molecules whose functions will be to prevent sepsis in hospitals or to distinguish between viral and bacterial infections.

For the later two projects, we're estimating that they would require about $20M in development of new 3D or cell-level RNA gaming interfaces and new experimental pipelines. So stay tuned... and of course if you have ~$20M to spend on the next level of citizen science, we'd love to hear from you.


PS. Purvesh gave his talk near the beginning of day 1 -- follow this link to see the raw video.
(Edited)
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rhiju, Researcher

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Separate comment -- Given how specific you were about deamination, do you happen to know a lab who would be interested in carrying out 4-6 cycles of experiments to test eterna designs for getting deaminated (or guiding deamination)?
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cynwulf28

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I did my undergraduate work with Dr. Barry Hoopengardner of CCSU. I am not sure if he would be able to do it all himself (questions of infrastructure/ funding/time), but he certainly has a vested interest in that sort of thing (I know he would interested if nothing else). He still does work though with several others in the field including Robert Reenan of Brown. Perhaps someone (myself?) could email one or both of them???
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rhiju, Researcher

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Worth a shot!
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cynwulf28

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 I had one other line of thought that I didn't include before (if only so as not to complicate things). Though I am no expert, I know that there is quite a lot going on on the DNA front these days. With much of the de novo innovations being in part directed or aided by RNAs (guide/cajal/ piwi/micro) and hybrid duplexes are sometimes made/used. many of the strategies that have been developed for Switch and Aptamer puzzles have analogous applications with DNA. 
Perhaps the interplay between RNA and DNA (e.g., how to silence a gene) may some day considered here. 
    The other thought along these lines is a new twist on aptamer/switch puzzles where one of the bound states help direct a nuclease/editase activity. 
     Either way, that's all I got for now. Thank you all!
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rhiju, Researcher

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Devs love these ideas  -- and hence the exploration of CRISPRi/CRISPRa, which involve using designed RNAs to program RNA/protein complexes that bind to double-stranded DNA. For us, we'd love to move forward but need a partner (or partners) with expertise in the method, ideally in living cells. Again, if you hear about labs who are interested, send them my way. :)
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cynwulf28

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For CRISPR i/a, I am assuming (inactivating/activating). If this is the case, then would the RNA be the active agent in inactivation/activation, or would it recruit something else to perform that action? I'm recalling the RNAinterference pathway: Argonauts, PIWI-RNAs, guide RNAs and especially microRNAs. 
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rhiju, Researcher

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Most simply the CRISPR/Cas9 complex would recruit or block RNA polymerase from transcribing the DNA gene specified by the CRISPR guide sequence. As you point out we could also be in the business of creating silencing RNAs -- that might be better for applications where we'd want to avoid the possibility of making any edits to the DNA genome..