One of the enduring questions in origin-of-life research is how the first biologically useful molecules could have become sufficiently concentrated to interact before cells, complete with enclosing membranes, had evolved. Dispersed throughout an ocean or pond, relatively fragile molecules such as RNA would have been unlikely to encounter one another often enough to sustain complex chemical reactions and would have remained exposed to environmental degradation. Some form of compartmentalisation therefore appears to have been an important intermediate stage between unorganised prebiotic chemistry and the first true cells.
Creationists routinely present this and other unanswered questions about abiogenesis as though they were evidence for supernatural intervention. The familiar argument is that, because scientists have not yet reconstructed every step between simple chemistry and the earliest life, an unexplained creator must have supplied whatever is missing. This is merely the false dichotomy and the god-of-the-gaps fallacy masquerading as an explanation. A gap in current scientific knowledge is not evidence that magic occurred inside it, and the history of science is largely a history of such gaps being progressively narrowed by evidence.
Research led by physicist Priya R. Banerjee of the University at Buffalo has now identified a potentially important natural mechanism that could have helped solve the problem of pre-cellular compartmentalisation. In a paper published in Nature Communications, Gable M. Wadsworth and colleagues compared the behaviour of RNA with that of single-stranded DNA carrying essentially equivalent nucleotide sequences. They found that RNA was markedly more inclined to gather spontaneously into microscopic, liquid-like droplets known as biomolecular condensates.
These condensates are not cells and are not enclosed by lipid membranes. Nevertheless, they could perform part of the function later assumed by cellular compartments: bringing molecules together in a confined space, increasing the likelihood of interactions and potentially providing some protection from hostile surroundings. The experiments showed that RNA began forming droplets at temperatures about 10 °C lower than the corresponding DNA and was also more prone to developing interconnected, gel-like molecular networks. Such networks might have retained and protected RNA more effectively than freely dispersed molecules could have done. The researchers used temperature-controlled microscopy, small-angle X-ray scattering and molecular-dynamics simulations to investigate the effect.
Remarkably, much of the difference can be traced to a very small chemical distinction between RNA and DNA. The ribose sugar in RNA carries a hydroxyl group at its 2′ position—the 2′-OH group—which is absent from the deoxyribose sugar of DNA. The experiments and computer simulations indicated that this group alters RNA’s interactions with magnesium ions and the surrounding water, helping RNA strands to associate with one another. When the researchers chemically modified the 2′-OH group, RNA’s tendency to condense weakened and the physical properties of the resulting droplets changed. A single chemical group on each sugar unit can therefore influence the emergence of structures many times larger than the individual molecules themselves.
The RNA world and the beginnings of cellular compartmentalisation. The RNA-world hypothesis proposes that, before modern cells evolved their present division of labour between DNA, RNA and proteins, RNA played a more central role in both heredity and chemical activity.This is especially relevant to the RNA-world hypothesis. Unlike DNA, RNA can both carry hereditary information and catalyse chemical reactions, making it a plausible participant in an early stage of evolution before the division of labour among DNA, RNA and proteins. One difficulty has always been explaining how sufficiently large concentrations of RNA could have persisted and interacted before lipid-bounded cells existed. Spontaneously forming RNA condensates offer a physically and chemically plausible part of the answer.
RNA is particularly significant because it can perform two functions essential to life:
- Information storage: Like DNA, the sequence of bases in an RNA molecule can encode information.
- Catalysis: Some RNA molecules, known as ribozymes, can accelerate chemical reactions, including reactions involving other RNA molecules.
Modern cells retain evidence of this ancient importance. RNA still carries genetic instructions from DNA to the cell’s protein-making machinery, and the catalytic core of the ribosome—the molecular machine that joins amino acids together—is composed principally of RNA. This supports the possibility that an earlier biological system relied much more heavily on RNA before DNA became the principal repository of genetic information and proteins became the principal biological catalysts.
However, an RNA world presents several problems. RNA is comparatively vulnerable to degradation, and molecules dispersed through water might rarely encounter one another in sufficient concentrations to sustain interconnected chemical reactions. Some means of concentrating, retaining and partly protecting RNA may therefore have been necessary before modern cells existed.
Condensates, vesicles and cells are not the same thing.
Structure Boundary Properties Biomolecular condensate No lipid membrane Forms when molecules separate from their surroundings and gather into a concentrated liquid-like droplet. It can concentrate particular molecules and may later become more gel-like. Fatty-acid vesicle A simple lipid boundary Can trap molecules and create an internal chemical environment distinct from its surroundings. Such vesicles are often investigated as models of early protocell membranes. Protocell Usually envisaged with a simple membrane A hypothetical intermediate combining some form of compartmentalisation with chemical reactions, growth or rudimentary heredity, but lacking the complexity of a true cell. Living cell A regulated cell membrane Maintains an organised metabolism, uses hereditary information, regulates its internal environment and can reproduce as part of an evolving population.
RNA condensates are therefore not cells, nor are they surrounded by membranes. Their importance lies in their ability to arise through ordinary physical interactions and concentrate RNA within a limited space. This could have increased the frequency with which RNA molecules encountered one another, retained useful reaction products and provided some protection from environmental damage.
Condensates and lipid vesicles need not represent competing explanations. Different forms of compartmentalisation may have operated together or in succession. RNA-rich droplets could, for example, have interacted with simple fatty-acid membranes or eventually become enclosed within them. Establishing whether anything resembling this occurred on the early Earth requires further evidence, but each experimentally demonstrated mechanism supplies another physically plausible step between dispersed prebiotic chemistry and the first membrane-bounded cells.
The boundary between non-living chemistry and life was therefore probably not crossed in one sudden event. It was more likely approached through a succession of systems that gradually acquired concentration, catalysis, heredity, compartmentalisation and the capacity for Darwinian evolution.
The researchers have not created life, nor have they demonstrated that these particular droplets existed on the early Earth. What they have shown is that ordinary molecular properties can cause RNA to organise itself into concentrated, partly protective compartments without membranes, genes, enzymes or supernatural direction. It is another example of researchers turning a supposed insurmountable obstacle into a testable scientific question—and discovering that chemistry itself provides mechanisms capable of narrowing the gap.
The paper in Nature Communications was accompanied by a news release by the University at Buffalo:
RNA droplets may have helped start life on Earth. A new study explains why they form
A tiny chemical difference helps make RNA better than DNA at condensing into liquid-like droplets under high temperatures and acidic conditions
It’s one of the origins of life’s chicken-or-the-egg problems: How could RNA have helped give rise to the first cells before there were cells to contain them?
Without the compartmentalization of a cell, it would have been extremely difficult for these vulnerable molecules to have found enough of each other in the proverbial primordial soup, let alone survive the harsh conditions of the early Earth.
The answer could lie in RNA’s ability to assemble together into liquid-like droplets, or condensates. These membraneless compartments could have concentrated RNA molecules, increasing opportunities for them to interact and potentially sheltering them from a hot and acidic environment.
Now, a new study led by the University at Buffalo is shedding light on what makes RNA particularly adept at forming these droplets. Published July 31 in Nature Communications under the journal’s early access guidelines, the study found that a tiny chemical difference between RNA and DNA helps explain why RNA more readily organizes into droplets when temperatures rise — and why those droplets are more prone to becoming rigid, gel-like networked structures.
These findings reveal, for the first time, how remarkably small changes in molecular chemistry can control the emergence of much larger, self-organized biomolecular structures like RNA condensates. They could allow us to eventually address even deeper questions, like whether these condensates helped bridge the gap between simple molecules and the earliest forms of life.
Professor Priya R. Banerjee, PhD, lead corresponding author
Department of Physics
The State University of New York at Buffalo
Buffalo, NY, USA.
The study was done in collaboration with Jerelle Joseph, PhD, assistant professor of chemical and biological engineering at Princeton University. It was supported by the National Institutes of Health, the National Science Foundation, and Hypothesis Fund.
Study addresses questions on RNA world theory
The work is part of Banerjee’s research related to RNA world theory, which suggests that RNA played a central role in originating life on Earth. RNA molecules can both carry genetic information and catalyze chemical reactions, which could have allowed them to perform the chemistry that eventually gave rise to DNA, proteins and the first cells.
But RNA world theory faces fundamental questions, including how unstable RNA could have persisted under harsh prebiotic conditions and how enough RNA molecules could have become concentrated in one place to interact before cells existed.
RNA droplets could provide an answer. A 2023 study led by Banerjee found that RNA tends to organize itself into liquid-like droplets under high temperatures.
Heat transforms clusters of RNA into liquid-like droplets. The study found that temperature can alter the physical properties of RNA condensates, allowing a more networked structure to relax into rounded droplets.Credit: Priya Banerjee/University at Buffalo
Building off that work, the current study compared RNA’s droplet forming abilities with single-stranded DNA containing essentially the same sequences.
In their experiments, Banerjee’s group showed that RNA began forming droplets at temperatures roughly 10 degrees Celsius lower than the corresponding DNA, showing that RNA had a stronger tendency to condense. They also found that RNA molecules more readily formed interconnected networks within the droplets, transforming the material from fluid-like to more gel-like, which could protect RNA better under harsh environmental conditions.
A key reason appears to lie in the fact that RNA and DNA differ chemically by just one oxygen atom per sugar unit. Each sugar unit in RNA contains a chemical group called a 2′-hydroxyl (2′-OH) that is absent in DNA.
Using temperature-controlled microscopy, small-angle X-ray scattering and molecular-dynamics simulations performed by the Joseph group, the team found that the 2′-OH appears to help RNA interact more strongly with magnesium ions and retain fewer water molecules around its backbone than DNA does. Those differences help RNA molecules come together more readily as temperatures rise, the researchers found.
The researchers further tested the 2′-OH's role by chemically modifying it to 2′-Ome, similar to what’s found in many natural RNA. Doing so weakened RNA's tendency to condense and altered whether the resulting condensates remained fluid or became gel-like.
This single oxygen-containing group on RNA’s sugar has a surprisingly powerful effect on whether these molecules come together, remain dynamic or become arrested into a gel-like material.
Dr Gable M. Wadsworth, PhD, co-first author
Department of Physics
The State University of New York at Buffalo
Buffalo, NY, USA.
[Dr Wadsworth] will join the University of Texas at El Paso as an assistant professor this fall.
The Banerjee lab is now taking the next step: engineering RNA droplets to perform some basic functions of cells such as biochemical reactions. They are attempting to program the droplets to function as active, dynamic, cell-sized compartments, providing a potential foundation for designing all-RNA synthetic cells.
These kinds of self-organizing RNA compartments were possibly a step along the way to single-cell organisms.
Professor Priya R. Banerjee, PhD.
Publication:
This research does not show that RNA condensates were the origin of life, still less that scientists have recreated that origin in the laboratory. What it does show is that a significant part of the supposed problem of pre-cellular organisation has a plausible natural solution. RNA molecules need not have remained helplessly dispersed in a uniform “primordial soup”; their own chemical properties could have caused them spontaneously to assemble into concentrated, partly protective compartments.
The result is especially instructive because the behaviour depends substantially upon something as small as RNA’s 2′-hydroxyl group. No external organiser is needed to gather the molecules together. Interactions among RNA, magnesium ions and water are sufficient to produce collective properties that are absent from the individual components. Organisation, concentration and gel formation can emerge from chemistry without foresight, planning or supernatural intervention.
The droplets are not cells, but that is precisely the point. Evolutionary transitions do not require a fully developed modern structure to appear in a single impossible leap. Intermediate systems need only provide some advantage over what preceded them. A condensate capable of concentrating RNA and protecting it long enough for further reactions would have supplied raw material upon which subsequent chemical selection could act. Later association with simple lipid vesicles could then have produced increasingly cell-like compartments.
Creationism contributes nothing to investigating this process. Declaring that a creator made the first life explains neither which reactions occurred nor how, where or under what conditions they happened. It generates no measurable mechanism and no testable prediction. By contrast, the RNA-condensate hypothesis can be examined experimentally, modified in response to results and rejected if the evidence fails to support it.
Another supposed refuge for a god of the gaps has therefore become smaller. The remaining questions are real and substantial, but they belong to chemistry, physics and evolutionary biology—not theology. As researchers continue to connect simple molecular behaviour with increasingly organised prebiotic systems, the origin of life looks less like an inexplicable act of magic and more like a natural process whose intermediate stages are gradually being brought within the reach of experimental science.
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