Developer(s) | Stanford University Carnegie Mellon University |
---|---|
Initial release | 2010 |
Available in | English |
Type | Game with a purpose, Puzzle |
Website | eternagame |
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]
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]
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.
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]
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]
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.
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.
Ribosomes are macromolecular machines, found within all cells, that perform biological protein synthesis. 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.
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.
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, though this ratio differs between prokaryotes and eukaryotes.
Rosetta@home is a volunteer computing project researching protein structure prediction on the Berkeley Open Infrastructure for Network Computing (BOINC) platform, run by the Baker lab. Rosetta@home aims to predict protein–protein docking and design new proteins with the help of about fifty-five thousand active volunteered computers processing at over 487,946 GigaFLOPS on average as of September 19, 2020. Foldit, a Rosetta@home videogame, aims to reach these goals with a crowdsourcing approach. Though much of the project is oriented toward basic research to improve the accuracy and robustness of proteomics methods, Rosetta@home also does applied research on malaria, Alzheimer's disease, and other pathologies.
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.
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.
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.
David Baker is an American biochemist and computational biologist who has pioneered methods to design proteins and predict their three-dimensional structures. He is the Henrietta and Aubrey Davis Endowed Professor in Biochemistry, an investigator with the Howard Hughes Medical Institute, and an adjunct professor of genome sciences, bioengineering, chemical engineering, computer science, and physics at the University of Washington. He was awarded the shared 2024 Nobel Prize in Chemistry for his work on computational protein design.
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.
A human-based computation game or game with a purpose (GWAP) is a human-based computation technique of outsourcing steps within a computational process to humans in an entertaining way (gamification).
Experimental approaches of determining the structure of nucleic acids, such as RNA and DNA, can be largely classified into biophysical and biochemical methods. Biophysical methods use the fundamental physical properties of molecules for structure determination, including X-ray crystallography, NMR and cryo-EM. Biochemical methods exploit the chemical properties of nucleic acids using specific reagents and conditions to assay the structure of nucleic acids. Such methods may involve chemical probing with specific reagents, or rely on native or analogue chemistry. Different experimental approaches have unique merits and are suitable for different experimental purposes.
Nucleic acid tertiary structure is the three-dimensional shape of a nucleic acid polymer. RNA and DNA molecules are capable of diverse functions ranging from molecular recognition to catalysis. Such functions require a precise three-dimensional structure. While such structures are diverse and seemingly complex, they are composed of recurring, easily recognizable tertiary structural motifs that serve as molecular building blocks. Some of the most common motifs for RNA and DNA tertiary structure are described below, but this information is based on a limited number of solved structures. Many more tertiary structural motifs will be revealed as new RNA and DNA molecules are structurally characterized.
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.
Numerous key discoveries in biology have emerged from studies of RNA, including seminal work in the fields of biochemistry, genetics, microbiology, molecular biology, molecular evolution, and structural biology. As of 2010, 30 scientists have been awarded Nobel Prizes for experimental work that includes studies of RNA. Specific discoveries of high biological significance are discussed in this article.
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.
Ruth Nussinov is an Israeli-American biologist born in Rehovot who works as a professor in the Department of Human Genetics, School of Medicine at Tel Aviv University and is the senior principal scientist and principal investigator at the National Cancer Institute, National Institutes of Health. Nussinov is also the editor in chief of the Current Opinion in Structural Biology and formerly of the journal PLOS Computational Biology.
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.