RNA World Hypothesis: RNA as the Monopoly of Early Life

By: Ashley Sheyn Buising (Paralogon) | Jared Von C. Santiago (Fosmid)

Before life had deoxyribonucleic acids (DNA) or proteins, the primordial world resembled that of the game of Monopoly. From a few paper bills, a complex economy unfolds, driven by reinvestment and strategy. Life on Earth may have followed a similar path. According to the RNA world hypothesis, ribonucleic acid (RNA) was life’s first “currency”, capable of storing information and catalyzing reactions that built more of itself. RNA set the stage for the rules that would govern all life on Earth– the GENESIS of all life on Earth. 

DNA and RNA are biomolecules that are responsible for storing and transmitting genetic information. DNA is a double-stranded helix with a deoxyribose sugar backbone and nitrogenous bases: adenine (A), guanine (G), cytosine (C), and thymine (T). In contrast, RNA is often single-stranded and has a ribose sugar backbone and has uracil (U) instead of thymine (T). In the contemporary central dogma of molecular biology, the following flow of genetic information is followed for the essential functions of present-day life: DNA → RNA → Protein (see figure 1; “present-day cells”). The RNA Hypothesis intends to answer the question: “Which came first?”, of what was the primordial molecule that kick-started life on Earth.  

RNA might have started life itself.

The RNA World Hypothesis is the most fascinating concept in the origin of life. It was not until the 1960s that the foundations behind the RNA World Hypothesis were set independently by Alexander Rich (1962), Carl Woese (1967), Francis Crick (1968), and Leslie Orgel (1968); stating that the first living entities were devoid of DNA and proteins, and were instead made of RNA (as cited in Lanzano, 2015). The ideas generally purport that RNA serves a dual function of acting as a repository of genetic information and a catalyst for biochemical reactions. And it was only decades later, with the discovery of catalytic RNA molecules (Ribozymes), that empirical evidence emerged to support this hypothesis. This breakthrough not only validated the model but led to the formal adoption of the term in scientific literature, a phrase first coined by Walter Gilbert in 1986.

Polynucleotides and Ribozymes: the Catalyst and the Code

In the 1980s, Ribozymes were first discovered by Tom Cech and Sid Altman, a portmanteau of RNA and enzymes– a pseudo-enzyme. Polynucleotides, unlike proteins, can both store genetic information and catalyze chemical reactions. As the single-stranded molecules can: (1) fold into highly elaborate structures; and (2) have base pairs that can bind metal ions for active sites in catalytic reactions– in short, they can bind like proteins do and have a binding site and substrate specificity, as enzymes do (see figure 2). This gives RNA the ability to catalyze (like in Figure 2, where it catalyzes the cleaving of another RNA) and self-replicate (see Figure 1; “RNA-based systems”); 

RNA World Hypothesis: Prebiotic Chemist’s Nightmare

However, while RNA’s dual ability seems a promising silver bullet to the obscurity of life’s origins, the RNA world hypothesis is not without its challenges. One of the prominent challenges is the “Prebiotic chemist’s nightmare”, which is an onslaught of problems with RNA as life’s first “currency” that continue to muddy the hypothesis. Khatib & Raslan (2021) summarize four key hindrances to the RNA world hypothesis: (1) RNA is too complex a molecule to have risen prebiotically; (2) RNA is an inherently unstable molecule; (3) catalytic functions are relatively rare properties of long RNA sequences only; and (4) the catalytic range of RNA is too limited. Regardless, science is a dynamic and ever-moving process of inquiry; what seems to be a hurdle can inspire groundbreaking advancements.

Through Science.

RNA World Hypothesis continues to grow as a relevant subject in both evolutionary genetics and biology. A recent breakthrough by Zhang et al. (2025) demonstrated that the prebiotic synthesis of RNA is still plausible despite the Prebiotic chemist’s nightmare. Isocyanide activation simulates the prebiotic environment of fluctuating geochemical factors where oligonucleotides and the reagents used are continually replenished, enabling efficient oligonucleotide activation that supports multiple cycles of ribozyme-catalyzed copying. 

RNA is the GENEsis.

The RNA World Hypothesis provides a compelling solution to the long-standing puzzle in the origin of life – What comes first? It resolves the paradox of how complex systems like DNA and proteins, which are interdependent, could have emerged. RNA may have served as the first self-sufficient molecule that was capable of replication and function, sparking the earliest forms of life. This unique potential of RNA, its ability to hold information and spark its own replication, became the stepping stone for the formulation of the RNA World Hypothesis. Despite the hurdles with this theory, science continues to invest in RNA’s story– as in the game of life, RNA might just be the first to have moved.