How Eterna players can generate 100,000 promising OpenCRISPR designs in just eight weeks

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Well, here we are, with a new challenge and an experimental capacity for analyzing 10 times as many designs as ever before.  Wow!

I can imagine that many experienced players rolled their eyes a bit when then saw the goal of ~100,000 submissions, thinking there was no way we could get so many players to generate so many solutions.  But really, there is method in this madness.  Hear me out. :-)

There are a total of 32 puzzles, most of which have a per-player limit of 150.  That means each of us has a potential for submitting ~5000 solutions.  I know of a handful of players who can actually do this with the tools they have available.  Five players generating ~5000 designs comes to a total of ~25,000 designs, which is more than twice as many as we've ever had in the past, but it is still far short of 100,000.

How is it possible for a single player to create 5000 designs in two months?  They don't all use the same techniques, but what they all have in common is having access to programs/scripts to do a lot of the heavy lifting of generating and/or evaluating possible designs.  What I want to do is to make one or more of these automation tools accessible to 100 players, instead of only 5.

Here's an example that has been rolling around in my head the last few days.  Say you have a design you think is promising.   Maybe you created it, or maybe another player created.  In either case, you bring it up in the game and decide on a way to experiment with variations.  You mark the bases you would like to modify with the black marker, and load the Awesome booster from the booster menu.  You then choose what kind of mutations you would like to see (mutations, deletions, ...) and what screening criteria (e.g. satisfies constraints with Vienna2) you would like applied.  You click on a button and BOOM! you have a list of all the designs that satisfy your request.

At this point, you can choose to scroll through the designs to see how they look in the game and trim the list down as much as you want.  When you are satisfied, you click another button to submit the remaining designs and ... (well it won't be BOOM!; maybe you should go take a nap) your computer will do that for you.

Jandersonlee has already laid much of the groundwork for a booster like this.  But it  will take more work to turn it into something that is easy accessible and useful to any player.  And that is really the whole point of this post -- to recruit players who are willing to contribute their time and skills to making this (or other ideas) into reality.  Typically, the skill in shortest supply is Javascript experience.  But a lot more than coding goes into software development, like figuring out a really good UI, testing, organizing, cheering, etc.

The floor is now open for discussion.  Let the Force be with you.
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Omei Turnbull, Player Developer

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Posted 3 years ago

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Eli Fisker

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Experiment Template - Science 101

I have an idea that I think can help us players design our own experiments. 

Really it is your idea, Omei. :)

I just transferred and rotated it a bit, just as if it was an RNA design. ;) 


Science Template Across Labs


I had long been claiming that the FMN aptamer had a favorite orientation in relation to the switching area. I knew I was right as scores the new labs that had the FMN orientated as I wished to see it, seems to go in the right direction. But I didn't have a way to demonstrate in a short and easy manner so everybody would understand. 

Omei demonstrated across different labs, how the different FMN aptamer orientation affected average fold change and max fold change. And put it in a easily viewable manner. 


Science Template Inside a Single Lab

I think we can snatch that template and adapt it to designs in a single lab with different groups of experiments run against each other. (I even suspect the template could be automated later.)

I have put up a google doc with a couple of examples of how to shift Omei's overview for a lab round until something that can be used to test hypothesis in a single lab: 

Science Template

I also put up the labs and their links in a spreadsheet. One could also put up hypothesis like this. 

Science Experiment Template

For those who haven't followed the related discussion, I have put up a collection of hypothesis I think is worth testing. Plus how to mark designs with hypothesis using # (Hashtags)
(Edited)
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Eli Fisker

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This mesh beautiful with my thoughts, Omei.

Dream demonstration. I love how you demonstrate the future booster.

And it is probably easier agreeing on hashtags between two players for starters. I even dissagree with my past self. :)

I think you are right on track with what you wish to see tested.

Just as I suspect the bases right around MS2 have a huge effect on the switch, I believe the ones around FMN to do so. I am currently using some I have generally seen in winning designs. In particular at the closed end of the aptamer.

You have suggested a method to test this systematically and I think we collectively holds the capacity to get the job done.


One more fun experiment
  • I have been considering just for the fun of it to throw in crossed GU's (can be done in two ways) at the 4 base spot you have highlighted in your last image - in a set of different designs.(At the non switching end of the aptamer)
This with the specific intention of destabilizing the area and see if we can get the CRISPR part to interact somehow with the Riboswitch part and if that would have any effect.
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Eli Fisker

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Additional thought on submission of designs in one go.

It would be helpful having something to tell them apart. So they are not all called the same. So either they get a 1,2,3 etc. Or as jandersonlee's script does - add a specifier for the specific mutation. So if base 34 is mutated to a G, the title would bear the mutation name G34.

Thought on the FMN surroundings experiment. I suspect it will be beneficial splitting the experiment of probing the bases around FMN into two sets. The 4 bases before and the 6 bases after. Here is why. The 6 bases after - at least for exclusion labs are partly decided by MS2.
(Edited)
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Eli Fisker

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Oh, I did get in basepairs around aptamers in the Hashtag Experiments doc. However I was mainly thinking of the closing base pairs. The whole area will be interesting. Adding it in.
(Edited)
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Omei Turnbull, Player Developer

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Re "It would be helpful having something to tell them apart. So they are not all called the same. So either they get a 1,2,3 etc. Or as jandersonlee's script does - add a specifier for the specific mutation. So if base 34 is mutated to a G, the title would bear the mutation name G34. ", I agree.  I figured that would be the responsibility of the booster script.
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MasterStormer, Player Developer

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How about using names also for data in the excel spreadsheet? For example:
"#DistanceFromAptamer Distance=5 Mutations=23G12C Note='Full of buldges'" Or will these be other parameters in the query?
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MasterStormer, Player Developer

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I want to point out that designing a ui and really thinking about how it would work from the user's perspective is just as important as coding it. If you have any ideas about how this would work, they aren't any less valuable than time spent working on these boosters.

I will post my ideas on this tomorrow, but I will just say for now that I think it would function like foldit, only that instead of your score going up, you're number of designs will go up.
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Gerry Smith

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I want to share one insight that came from another game I play (Quantum Moves - simulates moving atoms with laser tweezers)....the power of dropping bias.

The easiest way I have found to find bias is just to observe my own tendencies and then ask if these are in concert with the project's objectives.  If they are not, then that tendency (which is also highly likely to be held by others) is a bias to drop.

Here is an example.  Quantum Moves has 23 game levels - each simulating some aspect of quantum physics quandaries of quickly and stably moving atoms.  I noticed that I had a desire to get a top score in at least one of these levels.  So I had a tendency to focus on one game or a certain group of games where I thought I had a better chance of getting a top score.

Since each level incorporated different aspects of quantum physics aspects, not learning about the aspects of other game levels was not in concert with the project's goal.  Therefore the tendency to want to win at one level was a bias against cross level learning.

To remove this bias, I simply shifted my goal of wanting to get a highest score in a game to improving my worst score of all games.  This put my efforts more in alignment with the project's goals (of improvement) and also gave me two advantages that other players did not have.

The first advantage was better cross level learning.  By always focusing on my worse game, I improved the simulated quantum physics aspect that I was worst at.  And then could apply that to other games.

The second and probably more powerful advantage was to create better motivation for sustained engagement.  It was both easier to play this way, less frustrating and more fun.  So I played much more than other players.  

As a result of dropping this one bias, and after a year of playing in spite of the fact that I had never played any computer games before, I now have the top scores in Quantum Moves in 18 of the 23 levels, including all levels from 9 and up and being in the top 5 in the other five lower levels.

In eterna, the bias I have noticed within myself is to want to do the games myself without help to prove that I can.  In the lab, this has translated to a feeling wanting to create my own designs.

I assume others feel the same way.

This prevents cross person design collaboration during the most important time (labs).

How do we drop that?

 
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Eli Fisker

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Hi Gerry Smith!

I found your observations interesting. I think you have some real good insights here.

"Therefore the tendency to want to win at one level was a bias against cross level learning."

You are absolutely correct. To learn what will potentially work in future labs, we have to be willing to take a loss on score. It is helping in the EteRNA world that we haven't been getting lab coins for our designs for a long time.

The real game is figuring out how RNA folds. What it prefers.

If we can predict what it wants, we can help scientists make better tools for solving real world problems. 

You shifted your focus by will, to learn to overall improve your skills.

You did something else. You choose to improve your skills compared to yourself, which is really the best measure stick there is.

If we shift our focus to that there are people out there who are ill and that we actually hold it in our power to do something about it, I think it will be easier to drop the less healthy competition part. Which isn't good for us either.

We are not winning this game for ourselves. We are really trying to win this game for humanity.
(Edited)