A self-assembling molecule synthesized in a laboratory may resemble the earliest form of information-carrying biological material, a transitional stage between lifeless chemicals and the complex genetic architectures of life.

Called tPNA, short for thioester peptide nucleic acids, the molecules spontaneously mimic the shape of DNA and RNA when mixed together. Left on their own, they gather in shape-shifting strands that morph into stable configurations.

The molecules haven't yet achieved self-replication, the ultimate benchmark of life, but they hint at it. Best of all, their activities require no enzymes — molecules that facilitate chemical reactions, but didn't yet exist in the primordial world modeled by scientists seeking insight into life's murky origins.

"There have been many test tube experiments of evolving chemical sequences, but there hasn't been a system that on its own can form under enzyme-free conditions," said Reza Ghadiri, a Scripps Research Institute biochemist. "We satisfy some of the requirements of the long-term goal of having a purely chemical system that is capable of undergoing Darwinian evolution."

Among the co-authors of the paper describing tPNA, published Thursday in Science, is the late Leslie Orgel, a pioneering biochemist who hypothesized that DNA evolved from RNA, a simple information-carrying molecule that today forms the genomes of viruses and facilitates protein manufacture in organismal cells.

The so-called RNA world hypothesis is widely accepted among scientists, but requires several critical steps that have been satisfactorily explained in a laboratory only recently, if at all. One such step is the formation of RNA's chemical precursors. Another step involves their accumulation into RNA, which despite its relative simplicity, has resisted the attempts of scientists to synthesize it in primordial conditions.

A experiment published several weeks ago in Nature, in which a cycle of evaporation and condensation distilled a mix of primordial chemicals into several key RNA ingredients, has provided a plausible early answer to the problem of precursor formation. And the tPNA molecule in the current study may illuminate, at least in principle, how RNA might have emerged from these ingredients: in multiple stages, through a process of evolution.

"It's the pre-RNA world. There's a hypothesis that says RNA is so complicated, it couldn't have arisen de novo" — from scratch — "on early Earth," said study co-author Luke Leman, also a Scripps Research Institute biochemist. "So you need some more primitive genetic system that nature fiddled around with and finally decided to evolve into RNA."

Other researchers have tried to manufacture a similarly proto-genetic material, but their efforts have proved inefficient and relied on the chemical reaction-enhancing presence of enzymes which probably did not exist in Earth's early conditions. But according to the researchers, these experiments assumed that RNA — which resembles one-half the spiraling ladder form made famous by DNA — would assemble block by block, with each segment containing a fully-formed rung-and-backbone piece.

Instead, the researchers searched for a complete chemical spine to which the rungs, or nucleobases — A, T, C and G in the genetic code — could then attach. Rather than using the sugar-and-phosphate backbone found in RNA and DNA, they identified a peptide, or a small molecule composed of primordially present amino acids, that also functioned as a backbone.

"In terms of prebiotic chemistry, this is a conceptually different way of forming that genetic polymer," said Leman.

The nucleobases automatically adhered to the peptide in a loose fashion, detaching and attaching themselves until stable. When mixed with single strands of DNA or RNA in water at room temperature, the tPNA molecules arranged themselves in complementary strands, perhaps echoing the eventual ability of those genetic materials to duplicate themselves.

Ghadiri cautioned that tPNA shouldn't be seen as a direct analog of early life, but as demonstrating the plausibility of a similar system. "If you're thinking that at some point these types of molecules are going to hand off to the RNA world, they should have cross-pairing interactions, and be capable of interacting with RNA," he said. "We show both."

Antonio Lazcano, a National Autonomous University of Mexico biologist and expert in early Earth chemistry who was not involved in the study, called the work a synthetic biology breakthrough, but repeated Ghadiri's caveat that chemical bridges between the pre-RNA and RNA worlds are "completely unknown and can only be surmised."

According to University of Manchester organic chemist John Sutherland, who co-authored the *Nature *study showing how RNA's ingredients could have formed, the new research is less important in providing primordial insight than in furthering the eventual creation of life in a laboratory.

"Ghadiri's important and highly innovative new work potentially relates to the origin of life as we don't yet know it," said Sutherland. Life's emergence took billions of years, a process now being compressed into the passage of a few human generations. "The possibility that humans could come up with an alternative biology that outdoes that which produced us is a mind-freeing and mind-bending concept," he said.

The researchers are now searching for different types of peptide backbones that could support more complex and stable genetic structures.

"The next phase is to see whether these molecules are capable of self-replication," said Ghadiri. "That's another two or three years of work."

Asked how long it would take before fully synthetic life could be coaxed from an inert chemical mixture, Ghadiri said, "Soon. If not in our lifetime, then the next. In my opinion, it shouldn't be longer than that."

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Citation: "Self-Assembling Sequence-Adaptive Peptide Nucleic Acids." By Yasuyuki Ura, John M. Beierle, Luke J. Leman, Leslie E. Orgel, M. Reza Ghadiri. Science, Vol. 324 Issue 5933, June 12, 2009.

*Image: Science

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