It may emerge, unbidden, from the primordial ooze of a young planet, or it may be assembled within a modern laboratory. In either case, a cell—even a crude approximation of a cell—must satisfy certain requirements. First, the cell needs to define its extent, what’s in and what’s out, with a fatty acid membrane. Second, the cell must contain genetic material. Even a scrap of RNA will do, provided it is capable of replication.

For a really primitive cell, one lacking the sorts of complex enzymes that animate a modern cell, replication poses a seemingly unresolvable contradiction. The primitive cell, or protocell, can copy single-stranded RNA nonenzymatically in the presence of the magnesium ion. The magnesium ion, however, destabilizes simple fatty acid membranes. The very condition essential to replication also leads to dissolution.

This contradiction, a longstanding problem in cell biology, has been partly resolved by scientists at Massachusetts General Hospital. While working to create a synthetic cell—or, rather, recreate a prebiotically plausible protocell—these scientists discovered that citrate protects fatty acid membranes from the disruptive effects of high magnesium ion concentrations while allowing RNA copying to proceed. In addition, they found that citrate protects single-stranded RNA from degradation catalyzed by magnesium ions.

The researchers describe their work in a paper entitled “Nonenzymatic Template-Directed RNA Synthesis inside Model Protocells,” published November 28 in Science. According to the paper’s authors, the conditions made possible by citrate allow for the “chemical copying of RNA templates inside fatty acid vesicles, which in turn allows for an increase in copying efficiency by bathing the vesicles in a continuously refreshed solution of activated nucleotides.”

To protect fatty acid membranes from magnesium ions, the scientists used chelators, small molecules that bind tightly to metal ions. The chelators were also assessed for their ability to allow magnesium-catalyzed RNA assembly. While several chelators effectively stabilized fatty acid vesicles, only citrate allowed RNA chemistry to proceed.

RNA chemistry was assessed by placing short primer RNA strands bound to longer RNA templates into fatty acid vesicles. The unbound, single-strand portion of the template consisted of a sequence of cytosine nucleotides. In the presence of magnesium ion and a chelator, the researchers then added activated guanine, the nucleotide that base-pairs with cytosine in nucleic acids. Then the researchers looked for the desired reaction—diffusion of guanine nucleotides through the vesicle membrane to complete a double-stranded RNA molecule by binding to the cytosine nucleotides of the template.

To account for citrate’s success, study co-author Jack Szostak, Ph.D., said that it could be relevant that citrate covers only one face of the magnesium ion. He also observed that while citrate may be appropriate for creating artificial cells in the laboratory, it probably would not have been present in sufficient quantities in the early earth.

“We have shown there is at least one way to make RNA replication chemistry compatible with primitive, fatty-acid-based cell membranes, but this opens up new questions,” explained Dr. Szostak. “Our current best guess is there must have been some sort of simple peptides that acted in a similar way to citrate, and finding such peptides is something we are working on now.”

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