Scientists develop first examples of RNA that replicates itself indefinitely

One of the most enduring questions is how life could have begun on Earth. Molecules that can make copies of themselves are thought to be crucial to understanding this process as they provide the basis for heritability, a critical characteristic of living systems. Now, a pair of Scripps Research Institute scientists has taken a significant step toward answering that question. The scientists have synthesized for the first time RNA enzymes that can replicate themselves without the help of any proteins or other cellular components, and the process proceeds indefinitely.

The work was published on Thursday, January 8, 2009, in Science Express, the advanced, online edition of the journal Science.

In the modern world, DNA carries the genetic sequence for advanced organisms, while RNA is dependent on DNA for performing its roles such as building proteins. But one prominent theory about the origins of life, called the RNA World model, postulates that because RNA can function as both a gene and an enzyme, RNA might have come before DNA and protein and acted as the ancestral molecule of life. However, the process of copying a genetic molecule, which is considered a basic qualification for life, appears to be exceedingly complex, involving many proteins and other cellular components.

For years, researchers have wondered whether there might be some simpler way to copy RNA, brought about by the RNA itself. Some tentative steps along this road had previously been taken by the Joyce lab and others, but no one could demonstrate that RNA replication could be self-propagating, that is, result in new copies of RNA that also could copy themselves.
In Vitro Evolution

A few years after Tracey Lincoln arrived at Scripps Research from Jamaica to pursue her Ph.D., she began exploring the RNA-only replication concept along with her advisor, Professor Gerald Joyce, who is also dean of the faculty at Scripps Research. Their work began with a method of forced adaptation known as in vitro evolution. The goal was to take one of the RNA enzymes already developed in the lab that could perform the basic chemistry of replication, and improve it to the point that it could drive efficient, perpetual self-replication.

Lincoln synthesized in the laboratory a large population of variants of the RNA enzyme that would be challenged to do the job, and carried out a test-tube evolution procedure to obtain those variants that were most adept at joining together pieces of RNA.

Ultimately, this process enabled the team to isolate an evolved version of the original enzyme that is a very efficient replicator, something that many research groups, including Joyce’s, had struggled for years to obtain. The improved enzyme fulfilled the primary goal of being able to undergo perpetual replication. “It kind of blew me away,” says Lincoln.
Immortalizing Molecular Information

The replicating system actually involves two enzymes, each composed of two subunits and each functioning as a catalyst that assembles the other. The replication process is cyclic, in that the first enzyme binds the two subunits that comprise the second enzyme and joins them to make a new copy of the second enzyme; while the second enzyme similarly binds and joins the two subunits that comprise the first enzyme. In this way the two enzymes assemble each other — what is termed cross-replication. To make the process proceed indefinitely requires only a small starting amount of the two enzymes and a steady supply of the subunits.

“This is the only case outside biology where molecular information has been immortalized,” says Joyce.

Not content to stop there, the researchers generated a variety of enzyme pairs with similar capabilities. They mixed 12 different cross-replicating pairs, together with all of their constituent subunits, and allowed them to compete in a molecular test of survival of the fittest. Most of the time the replicating enzymes would breed true, but on occasion an enzyme would make a mistake by binding one of the subunits from one of the other replicating enzymes. When such “mutations” occurred, the resulting recombinant enzymes also were capable of sustained replication, with the most fit replicators growing in number to dominate the mixture. “To me that’s actually the biggest result,” says Joyce.

The research shows that the system can sustain molecular information, a form of heritability, and give rise to variations of itself in a way akin to Darwinian evolution. So, says Lincoln, “What we have is non-living, but we’ve been able to show that it has some life-like properties, and that was extremely interesting.”
Knocking on the Door of Life

The group is pursuing potential applications of their discovery in the field of molecular diagnostics, but that work is tied to a research paper currently in review, so the researchers can’t yet discuss it.

But the main value of the work, according to Joyce, is at the basic research level. “What we’ve found could be relevant to how life begins, at that key moment when Darwinian evolution starts.” He is quick to point out that, while the self-replicating RNA enzyme systems share certain characteristics of life, they are not themselves a form of life.

The historical origin of life can never be recreated precisely, so without a reliable time machine, one must instead address the related question of whether life could ever be created in a laboratory. This could, of course, shed light on what the beginning of life might have looked like, at least in outline. “We’re not trying to play back the tape,” says Lincoln of their work, “but it might tell us how you go about starting the process of understanding the emergence of life in the lab.”

Joyce says that only when a system is developed in the lab that has the capability of evolving novel functions on its own can it be properly called life. “We’re knocking on that door,” he says, “But of course we haven’t achieved that.”

The subunits in the enzymes the team constructed each contain many nucleotides, so they are relatively complex and not something that would have been found floating in the primordial ooze. But, while the building blocks likely would have been simpler, the work does finally show that a simpler form of RNA-based life is at least possible, which should drive further research to explore the RNA World theory of life’s origins.

The paper is titled “Self-sustained Replication of an RNA Enzyme,” and the work was supported by NASA and the National Institutes of Health, and the Skaggs Institute for Chemical Biology. For more information, see http://www.sciencemag.org/cgi/content/abstract/1167856.

19 thoughts on “Scientists develop first examples of RNA that replicates itself indefinitely

  1. Saying that a god exist just because you believe it exist is much less of an argument (if it can even be dignified with that name), and is exactly what all religions do, they imagine without any reason to imagine. And incredibly, to anyone with any sense of rationality, they call things that have been proven as a fact to be pseudo-arguments!!!Like the undeniable fact that the Earth isn’t just 10,000 years old.

    Your parody of the scientific method has been used by religious people for millennia to laugh at new and different ideas and in far too many cases religions were proven wrong. You said that the earth was 10,000 years old and we gave you dinosaur fossils. You said that the earth was the center of the universe with the sun orbiting the earth and we proved you wrong. You said only god could give life and we cloned the first mammal. Now you’re saying that we say “we think it is very common but we are unable to explicitly point out as already producing RNA replication” and arrogantly laugh because there is no factual proof (yet), I think even you can guess what the next step in this familiar cycle will be, right?

    You are saying that: Since there is no definite proof, then it must not be true. Ironically you don’t realize that if you were to apply this same logic to your faith it would deny the existense of your god.

    Religions are born and die all the time, it is only the people who didn’t accept to believe what they were told and did their own research, these are the people who have always existed and always will. Amen ;)

  2. Typical b.s. pseudo-argument of “secular activist” trolls: “In a universe with billions and billions of galaxies… our “lab conditions” should be present in abundance… and RNA replication already happened… only we don’t have any direct proof other than our “reasonable” faith in the lamp of the our “blind-luck” Genie, who by blind luck generated (through the “big bang” of course) – the “right” network of laws, producing the “right” complex set of causal chains, producing an abundance of “lab conditions” – which we are unable to explicitly point out explicitly as already producing RNA replication, etc, etc…

    But that’s ok, folks. Keep up the good work on your nice *engineering* projects!

    And by the way, maybe you don’t want to forget to throw in – as a back-up – some stuff with the “multiverse”, in case “billions and billions” do not suffice :-) The biologists have, unfortunately the poorest record when it comes to the percentage of articles that prove, in the end, to be error-free. Let’s keep our fingers crossed for this one, though :-)

  3. In a universe with billions and billions of galaxies, each with billions of different solar systems, it just makes the word “unlikely” almost disappear (especially if we consider the conditions which were used by the scientists mentioned in this article, these conditions aren’t that rare at all in our universe!).

    It is not that the universe has to match our experiment; it is the other way around. Nature simply has its laws for creating life, and we are still trying to replicate how this laws work by using the scientific method of trial and error. And after this discovery, we are getting closer and closer to finding out how life assembles itself from lifeless molecules. Simplicity becomes complex on its own thanks to the natural laws. And without the need of a creator.

    I, like any scientist, would ask for no less; this experiment has to be able to be repeated over and over again by anyone else who wants to try it. Otherwise it wouldn’t comply with one of the rules of the scientific method, in which case there would be no way to call this science.

  4. It is unlikely that natural conditions 100% identical with the “lab conditions” ever existed. Similar conditions may have existed, but then the scientists should prove, at a minimum, the stability of the phenomenon of “self-replication” with respect to a (variable) set of conditions. Let’s hope that the experiment itself can be… replicated, because other than that, it doesn’t prove much. Of course, some secular trolls will praise their “luck-god” for creating their “right conditions” somewhere… sometime… after the “lucky” big bang.

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