Two decades ago, on the recommendation of acclaimed astrophysicist Carl Sagan, NASA adopted a definition of life simply stating, “Life is a self-sustained chemical system capable of undergoing Darwinian evolution.” [1] While this definition is certainly consistent with life as we know it, its simplicity emphasizes how little we actually know about how life on Earth first arose. With the U.N.’s proclamation of 2011 as the “International Year of Chemistry,” Phillip Ball articulated that “How Did Life Begin?” remains #1 on the list of the top 10 unsolved mysteries.  Proponents argue that origins of life research “requires support for all the same reasons we support science like the Large Hadron Collider or the arts. [It] push[es] the boundaries of our understanding of the natural world in a field that absolutely requires cross-disciplinary research.” [2,3]

The RNA-World Hypothesis

Cells, which are the basic units of modern life, contain a soup-like mixture of proteins, nucleic acids, and other biomolecules enclosed in a cell membrane (Figure 1). Nucleic acids, namely DNA and RNA, are responsible for encoding and transmitting genetic material. DNA is responsible for storing and transmitting genetic information to new cells when the original cells replicate. RNA has many roles, including transmitting that genetic information from DNA to enable the production of proteins. These proteins perform various functions within the cell.  Some proteins provide structure and others, called enzymes, facilitate chemical reactions ranging from the digestion of food to the synthesis of DNA and RNA. Without these proteins, the cell could not grow or reproduce. When life first came about, though, it likely existed in a much simpler form, perhaps with a single compartmentalized biomolecule capable both of storing hereditary material and promoting useful chemical reactions. Origins of life research seeks to replicate the conditions on early Earth that facilitated the formation of these primitive cells, cells that could gradually undergo natural selection to more closely resemble life as we know it today.

Figure 1. The cell, which is the basic unit of modern life, contains DNA (responsible for encoding genetic information), RNA (responsible for translating that genetic information into proteins), and proteins which can act as enzymes to promote chemical reactions necessary for cell growth and reproduction.

The first scientific study of the chemical origins of life occurred in the 1950s. Stanley Miller and Harold Urey demonstrated that amino acids, the building blocks of proteins, could be created by passing electrical charges through mixtures of inorganic molecules (methane, ammonia, water and hydrogen) thought to exist on Earth around the time that life began. [4] While this landmark study triggered the birth of the field of “Origins of Life” research, a great gap remained between the prebiotic synthesis of simple building blocks and construction of any systems meeting the criteria of “life.”

The next great advance came three decades later with the discovery that some RNA molecules were capable of acting as enzymes to promote chemical reactions. Previously, RNA was presumed to act only passively to transmit genetic information to proteins. The revelation that it could do much more inspired Walter Gilbert to put forth the “RNA-World Hypothesis,” which states that because RNA can function both to transmit genetic information (like DNA) and to catalyze reactions (like proteins), it immediately follows that life likely originated from self-replicating RNA. [5,6] Researchers have since probed multiple aspects of this hypothesis, providing evidence to support it and seeking out areas of weakness for further examination.

John Sutherland and colleagues made a significant advance in 2009, when they reported the synthesis of activated ribonucleotides (the fundamental units of RNA chains) under prebiotically plausible conditions beginning from simple molecules likely to have existed in the primordial soup. [1,7] Other research efforts have focused on making longer chains of RNA, replicating existing RNA strands without the help of proteins, and examining the ability of some RNA strands to act as enzymes, all in an attempt to make the leap from inanimate molecules to self-sustaining systems. [1]

Where Prebiotic RNA Gets Stuck

Despite the attractive possibility of prebiotic RNA making the transition to life, several hurdles have, until now, limited the plausibility of the RNA-world model. While RNA can be copied in the absence of enzymes (Figure 2A), the original template RNA strand remains bound in a duplex with its complementary daughter strand. These strands must separate for replication to continue, but a temperature as high as that of boiling water may be necessary to separate the two strands of the duplex in the absence of enzymes. It would be very difficult to imagine that RNA replication on early Earth could occur at a reasonable rate if such extreme temperatures were necessary in each cycle. [9,10]

 Figure 2. (A) When RNA is copied, the original strand acts as a template for the formation of a complementary daughter strand. The original strand and daughter strand must then come apart, so the daughter strand can act as a template for the formation of a granddaughter strand that is an exact copy of the original. (B) Modern RNA contains only one type of linkage between units, but (C) when RNA is copied without enzymes, a mixture of two types of linkages results.

Furthermore, when RNA is copied in the absence of enzymes, the ribonucleotides are randomly connected at either of two different sites, forming a heterogeneous RNA backbone (Figure 2C). The RNA in modern cells is, however, formed exclusively by linking at one site (Figure 2B). [8] It has been difficult to suggest that faithful transmission of hereditary information could occur in a prebiotic system if all the RNA had an inconsistent linking pattern. [8,9,10]

Forging the Correct Link

Two research groups have, however, recently reported complementary approaches to the barriers described above. Professor Jack Szostak and colleagues at Harvard University and Massachusetts General Hospital demonstrated that, while random incorporation of mixed linkages (Figure 2C) into functional RNAs reduced their efficacy, the impact was not as catastrophic as originally anticipated. RNAs with mixed linkages showed activity reductions as small as 20%. [11] Szostak’s team further demonstrated that including a mixture of the two linkages reduced the temperature necessary for strand separation during RNA synthesis, making this repeated separation during replication easier to imagine. (Figure 2A) The reduced temperatures necessary for the replication of the mixed backbone RNAs on prebiotic Earth, paired with their demonstrated potential to promote useful reactions, provides support for the plausibility of their existence in an RNA-world. [11]

 Figure 3.  (A) One of the potential sites for linking RNA units could be selectively blocked. (B) Once the site was blocked, the RNA unit could selectively form a link at the site observed in modern RNA strands, and (C) the blocking group could be removed to generate free RNA.

Attacking the problem from a different angle, Professor John Sutherland and his colleagues at the UK’s Medical Research Council Laboratory of Molecular Biology demonstrated that one of the potential sites for linking RNA units could be selectively blocked under prebiotically plausible reaction conditions (Figure 3). Once the site was blocked, the RNA unit could selectively form a link at the site observed in modern RNA strands. Once the linkage was made between RNA units, the blocking groups could be readily removed to generate a free RNA strand, thus producing RNA strands with only one linkage type, like we see in modern RNA. [12]

Implications for the Origin of Life

Taken together, these recent reports show a plausible path by which enrichment of a single type of linkage in RNA strands could come about on early Earth while demonstrating that RNA strands containing a modest mixture of two different types of linkages could still carry information and act as functional catalysts. One can imagine that, with these properties, heterogeneously-linked but self-replicating RNA strands could gradually transition into a homogeneously-linked system subject to molecular selection over time. While many questions remain in the pursuit to understand the origins of life on Earth, the results described here provide a significant degree of support for the RNA-world hypothesis, and offer inspiration for scientists to continue this research and attempt to demonstrate a complete and coherent path from inanimate molecules to life.

C. Rose Kennedy is a PhD student in the Department of Chemistry and Chemical Biology at the Harvard University.

References:

[1] Joyce G.F. Deamer D.W. Fleischaker G. Origins of Life: The Central Concepts. Jones and Bartlett; Boston: 1994. Foreword.

[2] Ball, P. “10 Unsolved Mysteries.” Scientific American 305. 48 (2011): 48-53. DOI:10.1038/scientificamerican1011-48

[3] Powner, M. W. Interview by Stephen Davey “Asking Original Questions” Nature Chemistry 5. 5 (2013): 355-357. DOI:10.1038/nchem.1629

[4] Miller, S. L. “A Production of Amino Acids Under Possible Primitive Earth Conditions.” Science 117. 3046 (1953): 528–529. DOI: 10.1126/science.117.3046.528

[5] Gilbert, W. “Origin of life: The RNA world” Nature 319. 6055 (1986): 618. DOI:10.1038/319618a0

[6] Ricardo, A.; Szostak, J. W. “Origin of Life on Earth” Scientific American 301, 3 (2009): 54-61. http://dx.doi.org/10.1038%2Fscientificamerican0909-54

[7] Powner, M. W.; Gerland^, B.; Sutherland, J. D. ”Synthesis of activated pyrimidine ribonucleotides in prebiotically plausible conditions.” Nature 459, 7244 (2009): 239-242. DOI:10.1038/nature08013

[8] Ferris, J. P.; Ertem, G. “Oligomerization of ribonucleotides on montmorillonite: reaction of the 5′-phosphorimidazolide of adenosine.” Science  257. 5075 (1992): 1387-1389. DOI:10.1126/science.1529338

[9] Hernandez, A. R.; Piccirilli, J. A. “Chemical origins of life: Prebiotic RNA unstuck” Nature Chemistry 5. 5 (2013): 360–362. DOI:10.1038/nchem.1636

[10] “The ascent of molecules” Nature Chemistry 5. 5 (2013): 349. DOI: 10.1038/nchem.1647

[11] Engelhart, A. E.; Powner, M. W.; Szostak, J. W. “Functional RNAs exhibit tolerance for non-heritable 2′–5′ versus 3′–5′ backbone heterogeneity.” Nature Chemistry 5. 5 (2013): 390-394. doi:10.1038/nchem.1623

[12] Bowler, F. R.; Chan, C. K. W.; Duffy, C. D.; Gerland, B.; Islam, S.; Powner, M. W.; Sutherland, J. D.; Xu, J. “Prebiotically plausible oligoribonucleotide ligation facilitated by chemoselective acetylation.” Nature Chemistry 5. 5 (2013): 383-389. DOI: 10.1038/nchem.1626

For Further Discussion:

– Podcast: Mirsky, Steve. “Evolution Enclaves: Darwin the Botanist and Origins of Life Research.” Science Talk. 7 May 2008. Scientific American. <http://www.scientificamerican.com/podcast/episode.cfm?id=C49BBD9A-EF04-9EFE-6ABF8CD5BA21782B>
– Perspective Essay: Szostak, J. W.; Bartel, D. P.; Luisi, P. L. “Synthesizing Life.” Nature 409, 6818 (2001): 387-390. doi:10.1038/35053176

– Perspective Essay: Zimmer, C. “What Came Before DNA?” Discover (2004): <http://discovermagazine.com/2004/jun/cover#.UaeI9WTSNuE>

– Perspective Essay: Chen, I. A. “The Emergence of Cells During the Origin of Life.” Science 314. 5805 (2006): 1558-1559. DOI: 10.1126/science.1137541

– Perspective Essay: Shapiro, R. “A Simpler Origin for Life.” Scientific American 296, 6 (2007): 46-53. doi:10.1038/scientificamerican0607-46

– Online Educational Exhibit: “Understanding the RNA World” Exploring Life’s Origins, Museum of Science and NSF Discovery Corps Postdoctoral Fellowship: Visualizing the Chemical Origins of Life for Research and Education. < http://exploringorigins.org/>

– Online Video Clip: Kopec, C. “The Origin of Life – Abiogenesis” YouTube. YouTube. <http://www.youtube.com/watch?v=U6QYDdgP9eg>

– Editorial Introduction: Yarus, Michael. “Getting Past the RNA World: The Initial Darwinian Ancestor” Cold Spring Harbor Perspectives in Biology. 3. 4 (2011): 3590-3590. doi: 10.1101/cshperspect.a003590