What gave the first molecules their stability?

The origins of life remain a major mystery. How were complex molecules able to form and remain intact for prolonged periods without disintegrating? A team at ORIGINS, a Munich-based Cluster of Excellence, has demonstrated a mechanism that could have enabled the first RNA molecules to stabilize in the primordial soup. When two RNA strands combine, their stability and lifespan increase significantly.

In all likelihood, life on Earth began in water, perhaps in a tide pool that was cut off from seawater at low tide but flooded by waves at high tide. Over billions of years, complex molecules like DNA, RNA and proteins formed in this setting before, ultimately, the first cells emerged. To date, however, nobody has been able to explain exactly how this happened.

"We know which molecules existed on the early earth," says Job Boekhoven, Professor of Supramolecular Chemistry at the Technical University of Munich (TUM). "The question is: Can we use this to replicate the origins of life in the lab?" The team led by Boekhoven at the ORIGINS Cluster of Excellence is primarily interested in RNA. "RNA is a fascinating molecule," says Boekhoven. "It can store information and also catalyze biochemical reactions." Scientists therefore believe that RNA must have been the first of all complex molecules to form.

The problem, however, is that active RNA molecules are composed of hundreds or even thousands of bases and are very unstable. When immersed in water, RNA strands quickly break down into their constituent parts -- a process known as hydrolysis. So, how could RNA have survived in the primordial soup?

How did double strands form in the primordial soup?

In laboratory testing, the researchers from TUM and LMU used a model system of RNA bases that join together more easily than naturally occurring bases in our cells today. "We didn't have millions of years available and wanted an answer quickly," explains Boekhoven. The team added these fast-joining RNA bases into a watery solution, provided an energy source and examined the length of the RNA molecules that formed. Their findings were sobering, as the resulting strands of up to five base pairs only survived for a matter of minutes.

The results were different, however, when the researchers started by adding short strands of pre-formed RNA. The free complementary bases quickly joined with this RNA in a process called hybridization. Double strands of three to five base pairs in length formed and remained stable for several hours. "The exciting part is that double strands lead to RNA folding, which can make the RNA catalytically active," explains Boekhoven. Double-stranded RNA therefore has two advantages: it has an extended lifespan in the primordial soup and serves as the basis for catalytically active RNA.

But how could a double strand have formed in the primordial soup? "We're currently exploring whether it's possible for RNAs to form their own complementary strand," says Boekhoven. It is conceivable for a molecule comprising three bases to join with a molecule comprising three complementary bases -- the product of which would be a stable double-strand. Thanks to its prolonged lifespan, further bases could join with it and the strand would grow.

Evolutionary advantage for protocells

Another characteristic of double-stranded RNA could have helped bring about the origin of life. It is firstly important to note that RNA molecules can also form protocells. These are tiny droplets with an interior fully separated from the outside world. Yet, these protocells do not have a stable cell membrane and so easily merge with other protocells, which causes their contents to mix. This is not conducive to evolution because it prevents individual protocells from developing a unique identity. However, if the borders of these protocells are composed of double-stranded DNA, the cells become more stable and merging is inhibited.

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Modeling the origins of life: New evidence for an 'RNA World'

Charles Darwin described evolution as "descent with modification." Genetic information in the form of DNA sequences is copied and passed down from one generation to the next. But this process must also be somewhat flexible, allowing slight variations of genes to arise over time and introduce new traits into the population.

But how did all of this begin? In the origins of life, long before cells and proteins and DNA, could a similar sort of evolution have taken place on a simpler scale? Scientists in the 1960s, including Salk Fellow Leslie Orgel, proposed that life began with the "RNA World," a hypothetical era in which small, stringy RNA molecules ruled the early Earth and established the dynamics of Darwinian evolution.

New research at the Salk Institute now provides fresh insights on the origins of life, presenting compelling evidence supporting the RNA World hypothesis. The study, published in Proceedings of the National Academy of Sciences (PNAS) on March 4, 2024, unveils an RNA enzyme that can make accurate copies of other functional RNA strands, while also allowing new variants of the molecule to emerge over time. These remarkable capabilities suggest the earliest forms of evolution may have occurred on a molecular scale in RNA.

The findings also bring scientists one step closer to re-creating RNA-based life in the laboratory. By modeling these primitive environments in the lab, scientists can directly test hypotheses about how life may have started on Earth, or even other planets.

"We're chasing the dawn of evolution," says senior author and Salk President Gerald Joyce. "By revealing these novel capabilities of RNA, we're uncovering the potential origins of life itself, and how simple molecules could have paved the way for the complexity and diversity of life we see today."

Scientists can use DNA to trace the history of evolution from modern plants and animals all the way back to the earliest single-celled organisms. But what came before that remains unclear. Double-stranded DNA helices are great for storing genetic information. Many of those genes ultimately code for proteins -- complex molecular machines that carry out all sorts of functions to keep cells alive. What makes RNA unique is that these molecules can do a bit of both. They're made of extended nucleotide sequences, similar to DNA, but they can also act as enzymes to facilitate reactions, much like proteins. So, is it possible that RNA served as the precursor to life as we know it?

Scientists like Joyce have been exploring this idea for years, with a particular focus on RNA polymerase ribozymes -- RNA molecules that can make copies of other RNA strands. Over the last decade, Joyce and his team have been developing RNA polymerase ribozymes in the lab, using a form of directed evolution to produce new versions capable of replicating larger molecules. But most have come with a fatal flaw: they aren't able to copy the sequences with a high enough accuracy. Over many generations, so many errors are introduced into the sequence that the resulting RNA strands no longer resemble the original sequence and have lost their function entirely.

Until now. The latest RNA polymerase ribozyme developed in the lab includes a number of crucial mutations that allow it to copy a strand of RNA with much higher accuracy.

In these experiments, the RNA strand being copied is a "hammerhead," a small molecule that cleaves other RNA molecules into pieces. The researchers were surprised to find that not only did the RNA polymerase ribozyme accurately replicate functional hammerheads, but over time, new variations of the hammerheads began to emerge. These new variants performed similarly, but their mutations made them easier to replicate, which increased their evolutionary fitness and led them to eventually dominate the lab's hammerhead population.

"We've long wondered how simple life was at its beginning and when it gained the ability to start improving itself," says first author Nikolaos Papastavrou, a research associate in Joyce's lab. "This study suggests the dawn of evolution could have been very early and very simple. Something at the level of individual molecules could sustain Darwinian evolution, and that might have been the spark that allowed life to become more complex, going from molecules to cells to multicellular organisms."

The findings highlight the critical importance of replication fidelity in making evolution possible. The RNA polymerase's copying accuracy must exceed a critical threshold to maintain heritable information over multiple generations, and this threshold would have risen as the evolving RNAs increased in size and complexity.

Joyce's team is re-creating this processin laboratory test tubes, applying increasing selective pressure on the system to produce better-performing polymerases, with the goal of one day producing an RNA polymerase that can replicate itself. This would mark the beginnings of autonomous RNA life in the laboratory, which the researchers say could be accomplished within the next decade.

The scientists are also interested in what else might occur once this mini "RNA World" has gained more autonomy.

"We've seen that selection pressure can improve RNAs with an existing function, but if we let the system evolve for longer with larger populations of RNA molecules, can new functions be invented?" says co-author David Horning, a staff scientist in Joyce's lab. "We're excited to answer how early life could ratchet up its own complexity, using the tools developed here at Salk."

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Mimas' surprise: Tiny moon of Saturn holds young ocean beneath icy shell

Hidden beneath the heavily cratered surface of Mimas, one of Saturn's smallest moons, lies a secret: a global ocean of liquid water. This astonishing discovery, led by Dr. Valéry Lainey of the Observatoire de Paris-PSL and published in the journal Nature, reveals a "young" ocean formed just 5 to 15 million years ago, making Mimas a prime target for studying the origins of life in our Solar System.

"Mimas is a small moon, only about 400 kilometers in diameter, and its heavily cratered surface gave no hint of the hidden ocean beneath," says Dr Nick Cooper, a co-author of the study and Honorary Research Fellow in the Astronomy Unit of the School of Physical and Chemical Sciences at Queen Mary University of London.

"This discovery adds Mimas to an exclusive club of moons with internal oceans, including Enceladus and Europa, but with a unique difference: its ocean is remarkably young, estimated to be only 5 to 15 million years old."

This young age, determined through detailed analysis of Mimas's tidal interactions with Saturn, suggests the ocean formed recently, based on the discovery of an unexpected irregularity in its orbit.

As a result, Mimas provides a unique window into the early stages of ocean formation and the potential for life to emerge.

"The existence of a recently formed liquid water ocean makes Mimas a prime candidate for study, for researchers investigating the origin of life," explains Dr Cooper.

The discovery was made possible by analysing data from NASA's Cassini spacecraft, which meticulously studied Saturn and its moons for over a decade.

By closely examining the subtle changes in Mimas's orbit, the researchers were able to infer the presence of a hidden ocean and estimate its size and depth.

Dr Cooper continues: "This has been a great team effort, with colleagues from five different institutions and three different countries coming together under the leadership of Dr Valéry Lainey to unlock another fascinating and unexpected feature of the Saturn system, using data from the Cassini mission."

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Study uncovers potential origins of life in ancient hot springs

Newcastle University research turns to ancient hot springs to explore the origins of life on Earth.

The research team, funded by the UK's Natural Environmental Research Council, investigated how the emergence of the first living systems from inert geological materials happened on the Earth, more than 3.5 billion years ago.

Scientists at Newcastle University found that by mixing hydrogen, bicarbonate, and iron-rich magnetite under conditions mimicking relatively mild hydrothermal vent results in the formation of a spectrum of organic molecules, most notably including fatty acids stretching up to 18 carbon atoms in length.

Published in the journal Communications Earth & Environment, their findings potentially reveal how some key molecules needed to produce life are made from inorganic chemicals, which is essential to understanding a key step in how life formed on the Earth billions of years ago.

Their results may provide a plausible genesis of the organic molecules that form ancient cell membranes, that were perhaps selectively chosen by early biochemical processes on primordial Earth.

Fatty acids in the early stages of life

Fatty acids are long organic molecules that have regions that both attract and repel water that will automatically form cell-like compartments in water naturally and it is these types of molecules that could have made the first cell membranes.

Yet, despite their importance, it was uncertain where these fatty acids came from in the early stages of life.

One idea is that they might have formed in the hydrothermal vents where hot water, mixed with hydrogen-rich fluids coming from underwater vents mixed with seawater containing CO2.

The group replicated crucial aspects of the chemical environment found in early Earth's oceans and the mixing of the hot alkaline water from around certain types of hydrothermal vents in their laboratory.

They found that when hot hydrogen-rich fluids were mixed with carbon dioxide-rich water in the presence of iron-based minerals that were present on the early Earth it created the types of molecules needed to form primitive cell membranes.

Lead author, Dr Graham Purvis, conducted the study at Newcastle University and is currently a Postdoctoral Research Associate at Durham University.

He said: "Central to life's inception are cellular compartments, crucial for isolating internal chemistry from the external environment. These compartments were instrumental in fostering life-sustaining reactions by concentrating chemicals and facilitating energy production, potentially serving as the cornerstone of life's earliest moments.

The results suggest that the convergence of hydrogen-rich fluids from alkaline hydrothermal vents with bicarbonate-rich waters on iron-based minerals could have precipitated the rudimentary membranes of early cells at the very beginning of life.

This process might have engendered a diversity of membrane types, some potentially serving as life's cradle when life first started.

Principal Investigator Dr Jon Telling, Reader in Biogeochemistry, at School of Natural Environmental Sciences, added:

"We think that this research may provide the first step in how life originated on our planet. Research in our laboratory now continues on determining the second key step; how these organic molecules which are initially 'stuck' to the mineral surfaces can lift off to form spherical membrane-bounded cell-like compartments; the first potential 'protocells' that went on to form the first cellular life."

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Exploring the origins of life

Catalytic molecules can form metabolically active clusters by creating and following concentration gradients -- this is the result of a new study by scientists from the Max Planck Institute for Dynamics and Self-Organization (MPI-DS). Their model predicts the self-organization of molecules involved in metabolic pathways, adding a possible new mechanism to the theory of the origin of life. The results can help to better understand how molecules participating in complex biological networks can form dynamic functional structures, and provide a platform for experiments on the origins of life.

One possible scenario for the origin of life is the spontaneous organization of interacting molecules into cell-like droplets. These molecular species would form the first self-replicating metabolic cycles, which are ubiquitous in biology and common throughout all organisms. According to this paradigm, the first biomolecules would need to cluster together through slow and overall inefficient processes. Such slow cluster formation seems incompatible with how quickly life has appeared. Scientists from the department of Living Matter Physics from MPI-DS have now proposed an alternative model that explains such cluster formation and thus the fast onset of the chemical reactions required to form life.

"For this, we considered different molecules, in a simple metabolic cycle, where each species produces a chemical used by the next one," says Vincent Ouazan-Reboul, the first author of the study. "The only elements in the model are the catalytic activity of the molecules, their ability to follow concentration gradients of the chemicals they produce and consume, as well as the information on the order of molecules in the cycle," he continues. Consequently, the model showed the formation of catalytic clusters including various molecular species. Furthermore, the growth of clusters happens exponentially fast. Molecules hence can assemble very quickly and in large numbers into dynamic structures.

"In addition, the number of molecule species which participate in the metabolic cycle plays a key role in the structure of the formed clusters," Ramin Golestanian, director at MPI-DS, summarizes: "Our model leads to a plethora of complex scenarios for self-organization and makes specific predictions about functional advantages that arise for odd or even number of participating species. It is remarkable that non-reciprocal interactions as required for our newly proposed scenario are generically present in all metabolic cycles."

In another study, the authors found that self-attraction is not required for clustering in a small metabolic network. Instead, network effects can cause even self-repelling catalysts to aggregate. With this, the researchers demonstrate new conditions in which complex interactions can create self-organized structures.

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Origins of the building blocks of life

A new study led by Southwest Research Institute Research Scientist Dr. Danna Qasim posits that interstellar cloud conditions may have played a significant role on the presence of key building blocks of life in the solar system.

"Carbonaceous chondrites, some of the oldest objects in the universe, are meteorites that are thought to have contributed to the origins of life. They contain several different molecules and organic substances, including amines and amino acids, which are key building blocks of life that were critical to creating life on Earth. These substances are necessary to create proteins and muscle tissue," Qasim said.

Most meteorites are fragments of asteroids that broke apart long ago in the asteroid belt, located between Mars and Jupiter. Such fragments orbit the Sun -- sometimes for millions of years -- before colliding with Earth.

One of the questions Qasim and others are trying to answer is how amino acids got into the carbonaceous chondrites in the first place. Because most meteorites come from asteroids, scientists have attempted to reproduce amino acids by simulating asteroid conditions in a laboratory setting, a process called "aqueous alteration."

"That method hasn't been 100% successful," Qasim said. "However, the make-up of asteroids originated from the parental interstellar molecular cloud, which was rich in organics. While there's no direct evidence of amino acids in interstellar clouds, there is evidence of amines. The molecular cloud could have provided the amino acids in asteroids, which passed them on to meteorites."

To determine to what extent amino acids formed from asteroid conditions and to what extent they were inherited from the interstellar molecular cloud, Qasim simulated the formation of amines and amino acids as it would occur in the interstellar molecular cloud.

"I created ices that are very common in the cloud and irradiated them to simulate the impact of cosmic rays," explained Qasim, who conducted the experiment while working at NASA's Goddard Space Flight Center in Greenbelt, Maryland, between 2020 and 2022. "This caused the molecules to break up and recombine into larger molecules, which ultimately created an organic residue."

Qasim then processed the residue again by recreating asteroid conditions through aqueous alteration and studied the substance, looking for amines and amino acids.

"No matter what kind of asteroid processing we did, the diversity of amines and amino acids from the interstellar ice experiments remained constant," she said. "That tells us that interstellar cloud conditions are quite resilient to asteroid processing. These conditions could have influenced the distribution of amino acids we find in meteorites."

However, the individual abundances of amino acids doubled, suggesting the asteroid processing influences the amount of amino acids present.

"Essentially we have to consider both the interstellar cloud conditions and processing by the asteroid to best interpret the distribution," she said.

Qasim looks forward to studies of asteroid samples from missions such as OSIRIS-REx, which is currently on its way back to Earth to deliver samples from the asteroid Bennu here in September, and Hayabusa2, which recently returned from the asteroid Ryugu, to better understand the role the interstellar cloud played in distributing the building blocks of life.

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