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Brendan Monroe for Quanta Magazine


How did life’s myriad parts come together? At a minimum, the first life forms on Earth needed a way to store information and replicate. Only then could they make copies of themselves and spread across the world.

One of the most influential hypotheses states that it all began with RNA, a molecule that can both record genetic blueprints and trigger chemical reactions. The “RNA world” hypothesis comes in many forms, but the most traditional holds that life started with the formation of an RNA molecule capable of replicating itself. Its descendants evolved the ability to perform an array of tasks, such as making new compounds and storing energy. In time, complex life followed.

However, scientists have found it surprisingly challenging to create self-replicating RNA in the lab. Researchers have had some success, but the candidate molecules they have manufactured to date can only replicate certain sequences or a certain length of RNA. Moreover, these RNA molecules are themselves quite complicated, raising the question of how they might have formed through chance chemical means.

Nick Hud, a chemist at the Georgia Institute of Technology, and his collaborators are looking beyond biology to the role of chemistry in the development of life. Perhaps before biology arose, there was a preliminary stage of proto-life, in which chemical processes alone created a smorgasbord of RNAs or RNA-like molecules. “I think there were a lot of steps before you get to a self-replicating self-sustaining system,” Hud said.

In this scenario, a variety of RNA-like molecules could form spontaneously, helping the chemical pool to simultaneously invent many of the parts needed for life to emerge. Proto-life forms experimented with primitive molecular machinery, sharing their parts. The entire system worked like a giant community swap meet. Only once this system was established could a self-replicating RNA emerge.

Courtesy of Nicholas Hud

Nick Hud, a chemist at Georgia Tech, proposes that chemical evolution played a significant role in the origins of life.

At the heart of Hud’s proposal is a chemical means for generating a rich diversity of proto-life. Computer simulations show that certain chemical conditions can produce a varied collection of RNA-like molecules. And the team is currently testing the idea with real molecules in the lab; they hope to publish the results soon.

Hud’s group is leading the way for a number of researchers who are challenging the traditional RNA-world hypothesis and its reliance on biological rather than chemical evolution. In the traditional model, new molecular machinery was created using biological catalysts, known as enzymes, as is the case in modern cells. In Hud’s proto-life stage, myriad RNA or RNA-like molecules could form and change through purely chemical means. “Chemical evolution could have helped life get started without enzymes,” Hud said.

Hud and his collaborators have taken this idea one step further, suggesting that the ribosome, the only piece of biological machinery that is found in all living things today, emerged through chemistry alone. That’s an unconventional thought to many in the field, who think that the ribosome was born of biology.

If Hud’s team can create proto-life forms under conditions that might have existed on the early Earth, it would suggest that chemical evolution may have played a much more significant role in the origins of life than scientists expected. “Maybe there was some simpler form of evolution that preceded Darwinian evolution,” said Niles Lehman, a biochemist at Portland State University in Oregon.

The Pre-Darwinian World

When most people think about evolution, they think about Darwinian evolution, in which organisms compete with one another for limited resources and pass on genetic information to their offspring. Each generation undergoes genetic tweaks, and the most successful progeny survive to pass along their own genes. That mode of evolution dominates life today.

Carl Woese, a renowned biologist who gave us the modern tree of life, believed that the Darwinian era was preceded by an early phase of life governed by very different evolutionary forces. Woese thought it would have been nearly impossible for an individual cell to spontaneously come up with everything it needed for life. So he envisioned a rich diversity of molecules engaged in a communal existence. Rather than competing with each other, primitive cells shared the molecular innovations they invented. Together, the pre-Darwinian pool created the components needed for complex life, priming the early Earth for the emergence of the magnificent menagerie we see today.

Hud’s model takes Woese’s pre-Darwinian vision even further back in time, providing a chemical means for producing the molecular diversity that primitive cells needed. One proto-life form might have developed a way to make the building blocks it needed to make more of itself, while another might have found a way to harvest energy. The model differs from the traditional RNA-world hypothesis in its reliance on chemical rather than biological evolution.

According to RNA world, the first RNA molecules replicated themselves using a built-in enzyme called a ribozyme that was made of RNA. In Hud’s proto-life world, that task is accomplished through purely chemical means. The story begins with a chemical soup of RNA-like molecules. Most of these would have been short, as short strands are more likely to form spontaneously, but a few longer, more complex molecules might have come together as well. Hud’s model describes how the longer molecules might have replicated without the aid of an enzyme.

Olena Shmahalo/Quanta Magazine

Hud’s team has proposed a chemical method for replicating RNA. Heat separates long RNA strands (1). Short segments of complementary RNA bind to these strands (2) and are sewn together to create a new molecule (3). The cycle then begins again (4).

In Hud’s vision of a prebiotic world, the primordial RNA soup underwent regular cycles of heating and cooling in a thick, viscous solution. Heat separated the bound pairs of RNA, and the viscous solution kept the separated molecules apart for a while. In the interim, small segments of RNA, just a few letters in length, stuck to each long strand. The small segments eventually got sewn together, forming a new strand of RNA that matched the original long strand. The cycle then began again.

Over time, a pool of varied RNA-like molecules would have accumulated, some of them capable of simple functions, such as metabolism. And just like that, purely chemical reactions would have produced the molecular diversity needed to create Woese’s pre-Darwinian cornucopia of proto-life.

Hud’s team has been able to carry out the first stages of the replication process in the laboratory, although they can’t yet glue together the short segments without resorting to biological tools. If they can get over that hurdle, they’ll have created a versatile way of replicating any RNA that pops up.

Yet some scientists are skeptical that chemically mediated replication could work well enough to produce the pre-Darwinian world Hud describes. “I don’t know whether I believe it,” said Paul Higgs, a biophysicist at McMaster University in Hamilton, Ontario, who studies the origins of life. “It would have to be sufficiently accurate and rapid to pass on the sequence” — that is, it would need to produce new RNAs more quickly than they broke down and with enough fidelity to create near copies of the template molecule.

David Kaplan, Petr Stepanek and Ryan Griffin for Quanta Magazine; music by Kai Engel.

In Theory Video: David Kaplan explores the leading theories for the origin of life on our planet.

Chemical change on its own wouldn’t have been enough to trigger the emergence of life. The pool of proto-life would also have needed some kind of selection to make sure that useful molecules succeeded and multiplied. In their model, Hud’s team proposes that very simple proto-enzymes might have spread if they did something helpful for their maker and the larger community. For example, an RNA molecule that made more of its own building blocks would benefit itself and its neighbors by providing additional raw materials for replication. In computer simulations that Hud’s team performed, this type of molecule did indeed take root. “If a sequence comes along that does something useful, it can then be enriched in the pool,” Hud said.

Ribosomal Roots

One possible glimpse of the pre-Darwinian world can be seen in the ribosome, an ancient piece of molecular machinery that lies at the heart of our genetic code. It is an enzyme that translates RNA, which encodes genetic information, into proteins, which carry out the many chemical reactions in our cells.

The core of the ribosome is made of RNA. This feature makes the ribosome unique — the vast majority of enzymes in our cells are made from proteins. Both the ribosomal core and the genetic code are shared among all living things, suggesting that they were present very early in the evolution of life, perhaps before it crossed the Darwinian threshold.

Hud and his collaborator Loren Williams, also at Georgia Tech, point to the ribosome as support for their chemically dominated world. In a paper published last year, they made the controversial proposal that the core of the ribosome was created via chemical evolution. They also suggested that it arose before the first self-replicating RNA molecule. Perhaps the ribosomal core was a successful experiment in chemical evolution, they said. And after it took root in the pre-Darwinian soup, it crossed the Darwinian threshold and became an essential part of all life.

Their argument centers on the relative simplicity of the ribosomal core, more formally known as the peptidyl transferase center (PTC). The PTC’s job is to bring together amino acids, the building blocks of proteins. Unlike traditional enzymes, which speed up chemical reactions by using “fancy chemical tricks,” as Lehman put it, it works almost like a dehydrator. It coaxes two amino acids to bond simply by removing a molecule of water. “It’s kind of a poor way to drive a reaction,” Lehman said. “Protein enzymes typically rely on more powerful chemical strategies.”

Lehman notes that simplicity likely preceded power in the earliest stages of life. “When thinking about the origins of life, you have to think about simple chemistry first; any process with simple chemistry is probably going to be ancient,” he said. “I think that’s more powerful evidence than the fact that it’s [shared] among all life.”

Despite the powerful evidence, it’s still hard to imagine how the ribosomal core could have been created by chemical evolution. An enzyme that makes more of itself — like the replicator RNA of the RNA-world hypothesis — automatically creates a feedback loop, continually boosting its own production. By contrast, the ribosomal core doesn’t produce more ribosomal cores. It produces random chains of amino acids. It’s unclear how this process would encourage the production of more ribosomes. “Why would making random peptides make that thing better?” Higgs said.

Hud and his collaborators propose that RNA and proteins evolved in tandem, and those that figured out how to work together survived best. This idea lacks the simplicity of the RNA world, which posits a single molecule capable of both encoding information and catalyzing chemical reactions. But Hud suggests that facility might trump elegance in the emergence of life. “I think there’s been an overemphasis on what we call simplicity, that one polymer is simpler than two,” he said. “Maybe it’s easier to get certain reactions going if two polymers work together. Maybe it’s simpler for polymers to work together from the start.”

This article was reprinted on TheAtlantic.com.

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  • If molecules are replicating, and evolving through selection, why would you not call that life? What is in the "definition" of life that is missing…. (Please don't answer my question with a question… )

  • If chemical molecules replicate, and evolve through selection, why would you not call that life? What exactly is the dividing line between chemistry and biology, and how arbitrary is it?

  • An interesting idea, but I am confused about what part of this constitutes a "pre-Darwin" system, especially after this quote towards the end. "Hud and his collaborators propose that RNA and proteins evolved in tandem, and those that figured out how to work together survived best." Is that not the essence of Darwinism? And to be even more reductionist about it, at a simpler molecular level the creation of early molecules was still shaped by outside forces (chemical environment, supply of various elements, etc) that favored some over others…why is chemical evolution pre-Darwinian?

    I haven't read the original article.

  • @Bob, that's a good question and one that's under ongoing debate in the field. At a recent conference I attended on the origins of life, much of the dinner table discussions revolved around it.

  • Dear earthlings,

    Let me tell you, at a high level, how life emerged, so you needn't search in the dark any longer (though some of you more or less got it right) ;P

    First, there was an environment satisfying four crucial properties:

    – A rich chemistry
    – A chemistry that allows the spontaneous formation of membranes
    – A source of easily usable energy
    – A chemical process accessing the energy source and making the membranes grow

    These four properties are all that is needed for life to emerge, if the conditions remain stable in a big enough region of space-time!

    Indeed, in such an environment, some membranes will naturally grow. Once they reach a critical size, they will tend to tear and split, forming daughter membranes (the initial holes in the daughter membranes will tend to close as they have a greater affinity for themselves as for the surrounding water). Each daughter membrane will have approximately the same chemical mixture as its mother, albeit with some chance variations.

    At this stage, evolution kicks in: the membranes — actually, let's call them 'cells' from now on — the cells containing a more advantageous and self-sustaining chemical mixture will tend to reproduce more. Thus, even though the mixture inside the cells started off as being the same as that of the environment, it will slowly diverge from it, and develop a non-trivial metabolism.

    These cells can be regarded as the most primitive form of life; they don't even have an efficient information storage mechanism yet — they are storing their information through the relative abundance of molecules inside themselves.

    It is easy to see, however, how over time, evolution will take care of that, as information storage capacity will soon become a bottleneck. Some longer molecules will naturally get favored inside the cells, as they allow for more storage capacity. Before too long, some cells will use molecules that tend to form chains to allow them to have a more complex behavior.

    And voila! The rest is (pre-)history.

  • @Emily …. Not trying to get into a huge controversy here, but I am starting to think the term "life" might be what the physicists call metaphysical….
    @Rance…. yes, your confusion fits neatly into my Confusion

  • Bob, Rance, I agree these are excellent questions. The term "darwinian" has no specific definition, but when it's used, most people think of evolution in the sense of the neo-darwinian synthesis, as it was formulated in the 1940's or so. In this framework, evolution occurs by the accumulation of mutations in a linear polymer (e.g., DNA), selection of certain polymers over another through environmental pressure, and then exponential (Malthusian) amplification of the selected genotypes. In other words, this term has the connotation of vertical inheritance of point mutations, augmented by standard genetic processes such as linkage and drift. In the chemical system that Hud and colleagues is envisioning, there is no mutation per se, and inheritance is accomplished by very different (as of yet, unclear) mechanisms. That's why it is reasonable to describe it as "non-darwinian", and it portends a more complex dividing line between non-life and life.

  • Condescending Alien is not far off the mark. The first gene starts developing from the very beginning of the growth of membrane fragments. When the first cell is folded up by the ice, we see the start of genetics and subsequent metabolism but in a context where the goods produced are public rather than private. This leads to rapid convergence and is a more accurate description than the Darwinian idea of randomly varied and brutally selected competing organisms.

    Here is a description of the process in detail.

  • So is there anything new here? Christian de Duve wrote a whole book about this 20 years ago…Part 1 of Vital Dust is titled "The Age of Chemistry", and outlines the whole theory of natural selection operating in pre-biotic chemistry.

  • I'm surprised the article didn't mention the findings of Jeremy England…

  • Hud's work is interesting. But I don't think it is feasible.

    Higgs outline the main problem, RNA templating usually results in shorter strands and is a literary dead end for chemistry.

    On top of that there isn't any evolutionary fossils from a pre-RNA cell, while the modern DNA/protein cell has precisely a core RNA/protein machinery as a known fossil.

    Since there was so much hard, but unsupported, claims on The One And Only Pathway I hesitate to add another candidate. But it is striking that the so far only known strand elongating template replication mechanism that is tested is RNA PCR in an alkaline hydrothermal vent analog thermophoresis reactor, where pores constrain to elongation.

    So it needs an enzyme, or at least a catalyst, right? Not so fast, Keller et al has shown that such a vent in a Hadean ocean can do non-enzymatic glycolysis, so the chemical reactions are a lot less constrained than one can naively think. Besides, the gluconeogenesis – which should happen when you do product separation – substrate pyruvate has a catalytic pathway from vent H2/ocean CO2 in these vents, namely greigite.

    So we can ask again of it is a feasible set of pathways, but the hurdles – if any – are fewer.

  • I do not see the difference between chemical and biological evolution. Biology is merely chemistry writ large, i.e. biochemistry. Enzymes are still chemicals. DNA is a chemical. RNA is a chemical. All life is chemistry. Biology is the story of chemistry at a larger scale, obscuring some of the chemical details, but the difference between the two sciences does not mean there are two different worlds of life. Sorry, but I had problems appreciating the article due this false distinction between biological and chemical evolution.

  • Great article although I have to ask at what point do we say that chance and physical necessity are insufficient to explain the origin of life. Even if you could :(1)build the raw materials for RNA, and proteins namely nucleotides and amino acids (which you can't in a prebiotic soup); (2) make sure you only get amino acids that are left handed (3) make sure only peptide bonds form even though there would be numerous other competing molecules trying to bond with amino acids – how does chance guarantee that the right sequence will spontaneously emerge?
    If you take a 150 sequence long protein the number of possible sequences are 20 to the 150. The ratio of functioning to non-function protein sequences is extremely small, so how does chance guarantee that you will form a functioning protein. Secondly not any functioning protein will do, (proteins for bones would be useless for a proto cell) it would have to be very specific functioning proteins that RNA would have to code for. How does the RNA theory resolve these problems?

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