By playing EteRNA, you will participate in creating the first large-scale library of synthetic RNA designs. Your efforts will help reveal new principles for designing RNA-based switches and nanomachines - new systems for seeking and eventually controlling living cells and disease-causing viruses.
RNA is often called the "Dark Matter of Biology." While originally thought to be an unstable cousin of DNA, recent discoveries have shown that RNA can do amazing things. They play key roles in the fundamental processes of life and disease, from protein synthesis and HIV replication, to cellular control. However, the full biological and medical implications of these discoveries is still being worked out.
RNA is made of four nucleotides (A, C, Gand U, which stand for adenine, cytosine, guanine, and uracil). Chemically, each of these building blocks is made of atoms of carbon, oxygen, nitrogen, phosphorus, and hydrogen. When you design RNAs with EteRNA, you're really creating a chain of these nucleotides.
The most basic rules for folding RNA are similar to the famous rules for the DNA double helix that were figured out by Watson and Crick. There is a natural tendency for A, to stick to U, and for C, to stick to G. So when an RNA is synthesized, it doesn't just appear as a straight chain. It typically doubles back on itself to form helices that allow bases to pair up. The EteRNA project is trying to gain mastery over this folding phenomenon. It turns out that there are also other kinds of pairs (where A, sticks to G, for example) which can contribute to intricate 3D shapes and will be explored in the next generation of EteRNA.
Scientists do not yet understand all of RNA's roles, but we already know about a large collection of RNAs that are critical for life: (see the Thermus Thermophilus image representing following points)
mRNAs are short copies of a cell's DNA genome that get cut up, pasted, spliced, and otherwise remixed before getting translated into proteins.
rRNA forms the core machinery of an ancient machine, the ribosome. This machine synthesizes the proteins of your cells and all living cells, and is the target of most antibiotics
miRNAs (microRNAs) are short molecules (about 22-letters) that are used by all complex cells as commands for silencing genes and appear to have roles in cancer, heart disease, and other medical problems.
Riboswitches are ubiquitous in bacteria. They sense all sorts of small molecules that could be food or signals from other bacteria and turn on or off genes by changing their shapes. These are interesting targets for new antibiotics.
Ribozymes are RNAs that can act as enzymes. They catalyse chemical reactions like protein synthesis and RNA splicing, and provide evidence of RNA's dominance in a primordial stage of Life's evolution.
Retroviruses, like Hepatitis C, poliovirus, and HIV, are very large RNAs coated with proteins.
And much much more... shRNA, piRNA, snRNA, and other new classes of important RNAs are being discovered every year.
Why play Challenge Puzzles?
Challenge puzzles ask you to design RNA sequences that fold up into a target shape on your computer, similar to previous scientific discovery games such as Foldit. Many of these puzzles could be solved by existing computer programs. So why are you working on them? Two reasons. First, these puzzles provide a crucial training ground that bridges the gap between the tutorials and the Lab. Second, many existing computer programs take a huge amount of time to solve large RNAs, and you are very likely to find better, faster ways. Consider publishing your solution method
, which we can code up as an automated algorithm and test against existing computer programs.
Lab Puzzles are how Nature scores in EteRNA.The Lab asks you to solve the real RNA design problem. By actually creating your solutions, experimentally testing how they fold, and then giving you access to experiment results, the Lab exposes the gap between current computational models and reality. There has never been a game like this before. The Lab challenges you and your team to develop hypotheses which explain this gap -- and tests you on the next rounds. By advancing and testing hypotheses about when RNAs correctly fold in vitro, you are helping scientists understand the mysteries surrounding RNA folding and eventually paving the way towards new, complex, and medically useful biomolecules out of RNA.
EteRNA is starting with simple shapes like "The finger" and "The cross" to make sure you can nail the fundamentals. And then we'll be moving on to elaborate shapes like trees. And then molecules that switch folds when they sense a specific other piece of RNA. This might take a few weeks, or it might take a year -- we want to make sure we can ace these exercises.
After that, we will embark on one of a few epic projects -- perhaps we'll make the first RNA random-access memory for a computer. Or switches that enables cells to fluoresce if they start expressing cancer genes. Or how about a nanomotor? Or a nanoLED display? There are lots of options, and we'll let you propose your own and choose.
Finally, you'll start seeing a few other kinds of puzzles popping up in later stages: The ability to play with RNAs in three dimensions. The ability to see natural RNAs from bacteria, viruses, and humans; and challenges to predict their properties. Stay tuned.
What good stuff am I contributing by playing?
Besides purely biochemical advances, EteRNA is a radical experiment in citizen involvement in cutting-edge laboratory science. By playing the game and giving us feedback, you are helping us understand how to marshal large groups of people to solve complex problems on the Internet.