EteRNA

Last updated
Eterna
Developer(s) Stanford University
Carnegie Mellon University
Initial release2010
Available inEnglish
Type Game with a purpose, Puzzle
Website eternagame.org

Eterna is a browser-based "game with a purpose", developed by scientists at Carnegie Mellon University and Stanford University, that engages users to solve puzzles related to the folding of RNA molecules. [1] The project is supported by the Bill and Melinda Gates Foundation, Stanford University, and the National Institutes of Health. [2] Prior funders include the National Science Foundation. [3]

Contents

Similar to Foldit—created by some of the same researchers that developed Eterna—the puzzles take advantage of human problem-solving capabilities to solve puzzles that are computationally laborious for current computer models. The researchers hope to capitalize on "crowdsourcing" [4] and the collective intelligence [1] of Eterna players to answer fundamental questions about RNA folding mechanics. The top voted designs are synthesized in a Stanford biochemistry lab to evaluate the folding patterns of the RNA molecules to compare directly with the computer predictions, ultimately improving the computer models. [3] [5]

Ultimately, Eterna researchers hope to determine a "complete and repeatable set of rules" to allow the synthesis of RNAs that consistently fold in expected shapes. [6] Eterna project leaders hope that determining these basic principles may facilitate the design of RNA-based nanomachines and switches. [7] Eterna creators have been pleasantly surprised by the solutions of Eterna players, particularly those of non-researchers whose "creativity isn't constrained by what they think a correct answer should look like". [8]

As of 2016, Eterna has about 250,000 registered players. [9]

Gameplay

Players are presented with a given target shape into which an RNA strand must fold. The player can change the sequence by placing any of the four RNA nucleotides (adenine, cytosine, guanosine and uracil) at various positions; this can alter the free energy of the system and dramatically affect the RNA strand's folding dynamics. In Eterna, different restrictions, such as those on the number of certain bases and the number of the three base pair types, as well as locked bases, are sometimes imposed. A molecule is occasionally also included, which binds with the RNA and has critical effects on the free energy of the system. In some more advanced puzzles, players may be presented with two or three different target shapes at the same time; the single sequence the player produces must fold in the respective shapes under different conditions (presence or absence of a binding molecule).

Eterna puzzles are roughly classified into three types: Challenges, Player Puzzles, and Cloud Lab. Challenges are the puzzles prepared by the game-makers to introduce players to the workings of Eterna as well as to provide series of pre-set puzzles for players to attempt. Player puzzles are generated by players, and Cloud Lab is where the active, proposed and archived laboratory projects are presented for players to review, vote or attempt.

New players are guided through an initial puzzle progression which introduces the basic concepts of RNA structure and folding. As players proceed through puzzles of increasing complexity, the different game interface elements are described. After completing the 30 puzzles and earning all five Eterna Essentials badges, players gain access to the Cloud Lab where they can participate in laboratory research. Once players have completed a sufficient number of RNA puzzles, they unlock the chance to generate puzzles for other players.

Biomedical challenges

In 2016, Eterna launched its first biomedical challenge called OpenTB, an initiative to develop a new diagnostic device for tuberculosis. The project uses a gene expression "signature" discovered by Stanford researchers using public data, and aims to create an open source, paper-based diagnostic kit that can be easily deployed in clinics around the world. The development of the open source kit is a collaboration with MIT's Little Devices Lab. Players successfully designed RNAs to detect the gene signature by round 2 of the challenge, and as of February 2018 testing continues with real patient samples. [10]

Following the success of OpenTB, Eterna launched OpenCRISPR in August 2017, which challenges players to design single guide RNAs (sgRNAs) used in CRISPR gene editing. The goal of the project is to create a new class of sgRNAs that can be modulated by another small molecule (such as theophylline), allowing gene editing in the body to be turned on or off as needed. At the conclusion of round 1 in November 2017, players had submitted over 90,000 RNA designs for synthesis, the largest set of submissions to date. [11]

In response to the SARS-CoV-2 epidemic, Eterna joined the OpenVaccine collaboration to develop methods for stabilizing mRNA molecules that could be stored and shipped without the need for deep freezing. Players submitted 6000 designs for probing the stability of small RNA molecules at the nucleotide level, and used the results to design structured nanoluciferases that were tested for degradation in vitro and for protein expression in vivo. The OpenVaccine research resulted in novel methods and principles for designing stabilized mRNA therapeutics, including vaccines with potentially three times the current shelf life. [12] [13]

Synthetic biology

In 2019, Eterna launched the ribosome engineering project OpenRibosome in collaboration with the Jewett Lab at Northwestern University to enhance the folding of modified Escherichia coli ribosomes on the iSAT cell-free ribosome construction platform. The protein production of twenty 16S and twenty 23S sequences designed by players are being evaluated in a series of four feedback-based iterations. The ribosomes are being reengineered as molecular machines capable of synthesizing unique polymers. [14]

Accomplishments

See also

Related Research Articles

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Protein biosynthesis is a core biological process, occurring inside cells, balancing the loss of cellular proteins through the production of new proteins. Proteins perform a number of critical functions as enzymes, structural proteins or hormones. Protein synthesis is a very similar process for both prokaryotes and eukaryotes but there are some distinct differences.

<span class="mw-page-title-main">RNA</span> Family of large biological molecules

Ribonucleic acid (RNA) is a polymeric molecule that is essential for most biological functions, either by performing the function itself or by forming a template for the production of proteins. RNA and deoxyribonucleic acid (DNA) are nucleic acids. The nucleic acids constitute one of the four major macromolecules essential for all known forms of life. RNA is assembled as a chain of nucleotides. Cellular organisms use messenger RNA (mRNA) to convey genetic information that directs synthesis of specific proteins. Many viruses encode their genetic information using an RNA genome.

<span class="mw-page-title-main">Ribosome</span> Intracellular organelle consisting of RNA and protein functioning to synthesize proteins

Ribosomes are macromolecular machines, found within all cells, that perform biological protein synthesis. Ribosomal RNA is found in the ribosomal nucleus where this synthesis happens. Ribosomes link amino acids together in the order specified by the codons of messenger RNA molecules to form polypeptide chains. Ribosomes consist of two major components: the small and large ribosomal subunits. Each subunit consists of one or more ribosomal RNA molecules and many ribosomal proteins. The ribosomes and associated molecules are also known as the translational apparatus.

<span class="mw-page-title-main">Translation (biology)</span> Cellular process of protein synthesis

In biology, translation is the process in living cells in which proteins are produced using RNA molecules as templates. The generated protein is a sequence of amino acids. This sequence is determined by the sequence of nucleotides in the RNA. The nucleotides are considered three at a time. Each such triple results in addition of one specific amino acid to the protein being generated. The matching from nucleotide triple to amino acid is called the genetic code. The translation is performed by a large complex of functional RNA and proteins called ribosomes. The entire process is called gene expression.

<span class="mw-page-title-main">Ribosomal RNA</span> RNA component of the ribosome, essential for protein synthesis in all living organisms

Ribosomal ribonucleic acid (rRNA) is a type of non-coding RNA which is the primary component of ribosomes, essential to all cells. rRNA is a ribozyme which carries out protein synthesis in ribosomes. Ribosomal RNA is transcribed from ribosomal DNA (rDNA) and then bound to ribosomal proteins to form small and large ribosome subunits. rRNA is the physical and mechanical factor of the ribosome that forces transfer RNA (tRNA) and messenger RNA (mRNA) to process and translate the latter into proteins. Ribosomal RNA is the predominant form of RNA found in most cells; it makes up about 80% of cellular RNA despite never being translated into proteins itself. Ribosomes are composed of approximately 60% rRNA and 40% ribosomal proteins by mass.

The history of molecular biology begins in the 1930s with the convergence of various, previously distinct biological and physical disciplines: biochemistry, genetics, microbiology, virology and physics. With the hope of understanding life at its most fundamental level, numerous physicists and chemists also took an interest in what would become molecular biology.

<span class="mw-page-title-main">DNA origami</span> Folding of DNA to create two- and three-dimensional shapes at the nanoscale

DNA origami is the nanoscale folding of DNA to create arbitrary two- and three-dimensional shapes at the nanoscale. The specificity of the interactions between complementary base pairs make DNA a useful construction material, through design of its base sequences. DNA is a well-understood material that is suitable for creating scaffolds that hold other molecules in place or to create structures all on its own.

<span class="mw-page-title-main">Biomolecular structure</span> 3D conformation of a biological sequence, like DNA, RNA, proteins

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Nucleic acid structure prediction is a computational method to determine secondary and tertiary nucleic acid structure from its sequence. Secondary structure can be predicted from one or several nucleic acid sequences. Tertiary structure can be predicted from the sequence, or by comparative modeling.

<span class="mw-page-title-main">David Baker (biochemist)</span> American biochemist and computational biologist

David Baker is an American biochemist and computational biologist who has pioneered methods to predict and design the three-dimensional structures of proteins. He is the Henrietta and Aubrey Davis Endowed Professor in Biochemistry and an adjunct professor of genome sciences, bioengineering, chemical engineering, computer science, and physics at the University of Washington. He serves as the director of the Rosetta Commons, a consortium of labs and researchers that develop biomolecular structure prediction and design software. The problem of protein structure prediction to which Baker has contributed significantly has now been largely solved by DeepMind using artificial intelligence. Baker is a Howard Hughes Medical Institute investigator and a member of the United States National Academy of Sciences. He is also the director of the University of Washington's Institute for Protein Design.

<span class="mw-page-title-main">5S ribosomal RNA</span> RNA component of the large subunit of the ribosome

The 5S ribosomal RNA is an approximately 120 nucleotide-long ribosomal RNA molecule with a mass of 40 kDa. It is a structural and functional component of the large subunit of the ribosome in all domains of life, with the exception of mitochondrial ribosomes of fungi and animals. The designation 5S refers to the molecule's sedimentation velocity in an ultracentrifuge, which is measured in Svedberg units (S).

<span class="mw-page-title-main">Foldit</span> 2008 video game

Foldit is an online puzzle video game about protein folding. It is part of an experimental research project developed by the University of Washington, Center for Game Science, in collaboration with the UW Department of Biochemistry. The objective of Foldit is to fold the structures of selected proteins as perfectly as possible, using tools provided in the game. The highest scoring solutions are analyzed by researchers, who determine whether or not there is a native structural configuration that can be applied to relevant proteins in the real world. Scientists can then use these solutions to target and eradicate diseases and create biological innovations. A 2010 paper in the science journal Nature credited Foldit's 57,000 players with providing useful results that matched or outperformed algorithmically computed solutions.

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<span class="mw-page-title-main">Nucleic acid secondary structure</span>

Nucleic acid secondary structure is the basepairing interactions within a single nucleic acid polymer or between two polymers. It can be represented as a list of bases which are paired in a nucleic acid molecule. The secondary structures of biological DNAs and RNAs tend to be different: biological DNA mostly exists as fully base paired double helices, while biological RNA is single stranded and often forms complex and intricate base-pairing interactions due to its increased ability to form hydrogen bonds stemming from the extra hydroxyl group in the ribose sugar.

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<span class="mw-page-title-main">Nucleic acid quaternary structure</span>

Nucleic acidquaternary structure refers to the interactions between separate nucleic acid molecules, or between nucleic acid molecules and proteins. The concept is analogous to protein quaternary structure, but as the analogy is not perfect, the term is used to refer to a number of different concepts in nucleic acids and is less commonly encountered. Similarly other biomolecules such as proteins, nucleic acids have four levels of structural arrangement: primary, secondary, tertiary, and quaternary structure. Primary structure is the linear sequence of nucleotides, secondary structure involves small local folding motifs, and tertiary structure is the 3D folded shape of nucleic acid molecule. In general, quaternary structure refers to 3D interactions between multiple subunits. In the case of nucleic acids, quaternary structure refers to interactions between multiple nucleic acid molecules or between nucleic acids and proteins. Nucleic acid quaternary structure is important for understanding DNA, RNA, and gene expression because quaternary structure can impact function. For example, when DNA is packed into heterochromatin, therefore exhibiting a type of quaternary structure, gene transcription will be inhibited.

<span class="mw-page-title-main">RNA origami</span> Nanoscale folding of RNA

RNA origami is the nanoscale folding of RNA, enabling the RNA to create particular shapes to organize these molecules. It is a new method that was developed by researchers from Aarhus University and California Institute of Technology. RNA origami is synthesized by enzymes that fold RNA into particular shapes. The folding of the RNA occurs in living cells under natural conditions. RNA origami is represented as a DNA gene, which within cells can be transcribed into RNA by RNA polymerase. Many computer algorithms are present to help with RNA folding, but none can fully predict the folding of RNA of a singular sequence.

Rhiju Das is a computational biochemist and a professor of biochemistry and physics at Stanford University. Research in his lab seeks a predictive understanding of how RNA molecules and their complexes form molecular machines fundamental to life.

AlphaFold is an artificial intelligence (AI) program developed by DeepMind, a subsidiary of Alphabet, which performs predictions of protein structure. The program is designed as a deep learning system.

References

  1. 1 2 "RNA Game Lets Players Help Find a Biological Prize", John Markoff, The New York Times , January 10, 2011
  2. "Eterna - Invent Medicine". eternagame.org. Retrieved 2018-02-07.
  3. 1 2 "Rebooting science outreach" Archived 2018-07-18 at the Wayback Machine , Alan Chen, American Society for Biochemistry and Molecular Biology, June 2011
  4. "RNA research Eterna gets its game on", Erin Allday, San Francisco Chronicle , January 17, 2011
  5. "Play a game and engineer real RNA", John Roach, MSNBC , January 11, 2011
  6. "Treuille On Eterna - A Game Played By Humans, Scored By Nature" Archived 2012-10-04 at the Wayback Machine :Interview with Adrien Treuille, Byron Spice, Faculty & Staff News, Carnegie Mellon University, January 22, 2011
  7. About Eterna
  8. "Will NIH Embrace Biomedical Research Prizes?" Archived 2011-07-26 at the Wayback Machine , Michael Price, ScienceInsider, Science 19 July 2011
  9. 1 2 Taylor, Nick (18 February 2016). "Gamers crush algorithms in RNA structure design challenge". fiercebiotechit.com. Retrieved 23 February 2016.[ permanent dead link ]
  10. "OpenTB Lab Challenge".
  11. "OpenCRISPR Lab Challenge".
  12. "Online Gamers Could Help Vaccinate Billions". BloombergQuint. 15 October 2020. Retrieved 13 November 2020.
  13. Wayment-Steele, Hannah K; Kim, Do Soon; Choe, Christian A; Nicol, John J; Wellington-Oguri, Roger; Watkins, Andrew M; Parra Sperberg, R Andres; Huang, Po-Ssu; Participants, Eterna; Das, Rhiju (2021-09-14). "Theoretical basis for stabilizing messenger RNA through secondary structure design". Nucleic Acids Research. 49 (18): 10604–10617. doi:10.1093/nar/gkab764. ISSN   0305-1048. PMC   8499941 . PMID   34520542.
  14. "OpenRibosome Lab Challenge".
  15. "The Public, Playing a Molecule-Building Game, Outperforms Scientists", Rachel Wiseman, Wired Campus blog, The Chronicle of Higher Education , August 12, 2011
  16. Eterna Team. "Eterna results published in PNAS" . Retrieved 19 July 2014.
  17. Lee, Jeehyung; Kladwang, Wipapat; Lee, Minjae; Cantu, Daniel; Azizyan, Martin; Kim, Hanjoo; Limpaecher, Alex; Yoon, Sungroh; Treuille, Adrien; Das, Rhiju; Eterna participants (Jan 17, 2014). "RNA design rules from a massive open laboratory". PNAS. 111 (6): 2122–2127. Bibcode:2014PNAS..111.2122L. doi: 10.1073/pnas.1313039111 . PMC   3926058 . PMID   24469816.
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