From the Origin of Life to the Future of Medicine

Oceans churned with lava. Air filled thick with smoke. Asteroids stormed down incessantly. Life during the Hadean Eon four billion years ago was a struggle, and yet that was when it began.^1,2 With no fossil record dating this far back, biochemists ruminating over life’s inception have tried to reconstruct its origin story in the laboratory. While so much remains unknowable about life’s deep history, most trust that it kicked off with a timeless polymer—one that organisms continue to use today: ribonucleic acid (RNA).³

Cells of the modern world are seemingly too complex to have appeared spontaneously. “You use nucleic acids to make proteins, and then proteins to make nucleic acids, so the question is, ‘How do you boot up a system like that?’” said Philipp Holliger, a biochemist at the MRC Laboratory of Molecular Biology. The answer may lie with RNA. This molecule can store genetic information in its bases, undergo replication, and act like an enzyme to catalyze reactions, so in 1962 biologist Alexander Rich proposed that primordial life, crude and simple, could have emerged using this polymer alone.⁴

Demonstrating that an RNA world emerged out of a so-called “primordial soup” of organic molecules is not easy. “We can find explanations that work, but we will never be completely sure,” said Anna Medvegy, an evolutionary biology graduate student at Eötvös Loránd University in Hungary. “At the same time, the RNA world is, I would say, the most working theory right now,” she added.

Much of the research into RNA as the spark of life involves studying the versatile functions of natural and artificial RNAs to see if they have the capacity to serve both as enzymes and genomes as well as research into the conditions on the early planet that would have permitted RNA replication.⁵ These findings have led to RNA-based drug development and may lead to future applications in health and technology.

The Ribosome: A Lingering Relic of the RNA World

Perhaps the best proof that the RNA world existed can be found in every single cell on Earth. “The smoking gun really is the structure of the ribosome, which is absolutely central to all kinds of biology because it makes proteins,” Holliger said. These large complexes contain three or four RNA molecules coated in 50 or so proteins.⁶ When scientists removed the ribosome’s protein components in a piecemeal manner using enzymes or detergents, and just left its RNA, the ribosome still retained 20 to 40 percent of its functionality.⁷ “The bit that matters is RNA,” David Lilley, a molecular biologist at the University of Dundee said.

Since these cellular protein factories cannot function without RNA, researchers suspect that this nucleic acid is the oldest component of the ribosome. “People think that ribosome evolution proceeded by accretion,” whereby proteins deposited onto the RNA with time, Holliger explained. “You can look at the ribosome almost like an onion, with the core being the oldest, and then layers getting added to it,” he said.

One way to justify the existence of the RNA world is to explain how it would have transitioned into life as it is today. Scientists believe that once ribosomal RNA found a way to link together amino acids and fashion them into proteins, the RNA world would have swiftly ended. Proteins are easier to shape into enzymes because their amino acids come in 20 different flavors with different chemical properties.⁵ Lin Huang, an RNA biologist at Sun Yat-Sen University argued that the advent of proteins would have offered cells an evolutionary edge over ones relying solely on RNA. If a reaction needs a carboxylic acid, for example, proteins can use aspartic acid; if a reaction needs an amine, proteins call upon lysine. “They even have sulfur in the form of cysteine,” while RNA lacks this reactive element, Huang noted.

RNA by contrast, is more limited in its structure.⁷ It has four similarly shaped nucleotide bases and a backbone made of one of type of sugar molecule with a phosphate attached to it, so this nucleic acid could not catalyze the same variety of reactions as proteins, Lilley said.

Looking to nature, scientists found that ribosomal RNA may serve as a relic of RNA-led beginnings, but since ribosomal RNA can only synthesize proteins, their next challenge was to show that RNAs could be turned into various other enzymes, including ones essential for an RNA world to prosper.

Building Catalysts out of an RNA Code

Biochemists have tried to fashion artificial RNA catalysts by randomly mutating RNA strands and testing how well they perform different functions. In 2020, researchers at the University of Würzburg set out to invent an RNA molecule capable of linking together organic molecules by forming carbon-carbon bonds.⁸ Starting with RNA molecules containing 40 random nucleotides, they subjected them to 11 rounds of selection until they found the best candidate. Named methyltransferase ribozyme 1, it adds methyl groups to adenine substrates at a rate of one per minute, which is comparable to a protein-based enzyme called methyltransferase-like-3-14 that catalyzes a similar reaction at a rate of 0.2 to 0.6 per minute.⁹ Lilley said that if evolution in a test tube can produce a crude catalyst over such a short timeframe, scientists can infer that, in all likelihood, enzymatic RNAs formed over thousands or millions of years of evolution.

Making RNA catalysts is one thing, but since RNA’s building blocks are less diverse than those of protein, researchers want to show that this nucleic acid can catalyze specific reactions that would have been essential during the RNA world. James Attwater, a molecular biologist at University College London, and Holliger created an RNA enzyme that acts as a polymerase and produces copies of other RNA molecules, revealing that RNA has the capacity to conduct its own replication.¹⁰ “The fact that we can get such an activity from an artificial pool of random sequence RNA molecules indicates that activity might have been out there on the early Earth,” Attwater said.

Getting the Conditions Right for RNA Replication

Having established that RNA likely filled in for protein as enzymes at the dawn of life, the next challenge was to prove that, like DNA, RNA could reliably copy itself and propagate. However, once an RNA strand has been copied, it takes a great deal of energy to separate those two strands so that replication can reoccur.¹¹ What’s more, “it usually takes RNA enzymes on the order of hours to days to link building blocks together,” Attwater said, elaborating that “if you zip apart a double helix, what’s going to happen is the two strands are going to zip up back together before the strands can be copied,” which is a conundrum dubbed the “strand separation problem.”

In a study from May 2025, Attwater and Holliger modelled what conditions early Earth might have required to allow RNA to overcome this impediment and copy itself.¹² They figured that replication could occur with enough heat, acid, and short RNA building blocks. High temperatures would be needed to split the strands apart, and the acid’s protons could bind to and block the bases, which partially prevents the two strands from pairing back together.

However, to better prevent reannealing, short RNA sequences of just a few bases long, can help. Not only can they bind to separated RNA strands and prevent them zipping back together, they also serve as substrates for replication, Holliger noted. Having trialed short RNA strands of different lengths, Attwater said, “the easiest way to copy RNA on the early Earth would be to use building blocks that were around three letters long, which is particularly interesting because biology doesn’t use three-letter building blocks for replication nowadays, but it does use it within the ribosome for reading RNA to make proteins.” Since the ribosome is a relic of the RNA world, Attwater argued that it may be worth exploring whether there is a connection between using triplets for ancient replication and modern protein synthesis.

Besides these three ingredients, early RNA may have only copied itself in environments with oscillating conditions. “It’s not easy to achieve any of these early biological processes just sitting in water in an unchanging environment,” Attwater said. Similar to how scientists use cycles of hot and cold temperatures to split apart and copy DNA, respectively, in polymerase chain reactions, Attwater proposed that the RNA replication would have occurred with cycles of changing environmental conditions. These could have been alternating temperatures during day-night cycles, for example. “Freezing the reaction [at night] is a very important part of achieving replication because it concentrates these building blocks together in a frozen brine between ice crystals,” he said. Crowding all the reagents together ensures that they are all present to participate in replication.

RNA’s Next Chapter in Drug Development

Though RNA is often dubbed as merely an “intermediate” between DNA and protein, two biomolecules that scientists often harness for industry and medicine, research into RNA’s versatile properties suggest it could prove similarly attractive. Logistically, RNA is easier and cheaper to make than protein, Lilley said. “You can just make RNA by chemical synthesis. You don’t have to express it in bacteria,” he added. RNA molecules also fold into specific shapes depending on their sequence, making them valuable alternatives to other therapeutics, like monoclonal antibodies, which similarly bind to molecules by adopting a particular conformation.¹³ “They ought to be fantastically specific as therapeutic targets,” Lilley said.

Some RNA molecules in cells can silence genes by binding to messenger RNA and triggering their breakdown—a process called RNA interference. The drug Patisiran is an RNA molecule that works by exploiting this process to silence a gene underlying the fatal hereditary disorder transthyretin-mediated amyloidosis.¹⁴

As of 2025, seven therapeutic RNAs, including Patisiran, have been FDA approved. Nusinersen is another one of these. Doctors use it to treat a lethal genetic disorder called spinal muscular atrophy.¹⁵ Children with this condition experience progressive muscle weakness as a result of a fault in survival motor neuron protein 1 (SMN1). Nusinersen works by catalyzing the splicing of a related gene, SMN2, converting it into a functional replica of SMN1. “This little RNA manages to reprogram splicing so effectively,” Lilley said, that children experience a partial improvement in motor function with a simple spinal injection every six months.

In industry, Attwater hopes that chemists will harness synthetic RNA to build what are known as “orthogonal biological systems,” wherein biological processes, like replication, are emulated with synthetic molecules.¹⁶ “We are quite interested in how we can get these systems [to become] more complex and access capabilities that would otherwise be blocked within existing biological systems,” he said, explaining that these systems could allow researchers to develop enzymes and biological processes that modify molecules that cells don’t usually process. Beyond expanding the limits of chemistry, such a system, if self-replicating, could provide stronger evidence that RNA-based life may have sustained itself four billion years ago.

Though scientists cannot find traces of the RNA world from rocks surviving through the tumult of the Hadean Eon, laboratory recreations suggest this polymer had more than a fighting chance on early Earth.