To cook up life, just add citrate

Theory that RNA spawned first organisms gets boost from common compound

A common biochemical may help forge a missing link in a popular but unproven theory about how life got started.

One of the leading ideas of how loose molecules evolved to become complex cells begins with the hereditary molecule ribonucleic acid. Modern cells use RNA to make proteins, the workhorses of cellular function, but RNA likely preceded both proteins and DNA.

Evolution relies on reproduction, so any RNA-based origin-of-life theory has to include a way for RNA to copy itself. In previous work, biologist Jack Szostak of Harvard Medical School and colleagues showed that primitive RNA replication happens best when contained inside protocells. These containers have porous walls made of simple fat molecules — a far cry from modern cells, with their nearly impenetrable walls and sophisticated intake and excretion mechanisms.

Magnesium ions are also crucial to helping RNA replicate. Without them, the reaction is impractically slow. However, Szostak found that magnesium ions destroy the walls of his protocells, turning the fatty molecules into soap scum.

In a report in the Nov. 29 Science, Szostak and Katarzyna Adamala, also at Harvard, show that citrate, a relative of the citric acid in lemons and limes, protects protocell walls and allows RNA copying to proceed at a reasonable pace. Citrate latches onto three of the six available attachment points on the magnesium ion, leaving it open enough to assist the RNA reaction but too enclosed to interfere with the protocell walls.

Szostak and Adamala experimented by attaching to magnesium ions a number of molecules with structures similar to citrate, measuring their effect on both the pace of RNA replication and the integrity of the protocell wall. Citrate-bound magnesium had the best results, moving the reaction forward at almost half the pace of free magnesium ions and only slightly weakening the cell wall.

Szostak, though, seems far from declaring victory. “Our goal is finding some reasonable and continuous pathway from small molecules up to more complicated building blocks, then to cells that can start to evolve,” he says. “There might be many ways it can happen.”

He’s already experimenting with alternatives to magnesium and citrate because those compounds may not have been readily available on the early Earth. Iron might be able to take the place of magnesium, which is often bound up in minerals or in other forms unsuited to the RNA replication reaction. Instead of citrate, which may not have existed before more advanced cells evolved metabolic processes to create it, Szostak is thinking of using a peptide. These molecules are chains of amino acids that are shorter than proteins.

At least one origin-of-life expert thinks Szostak’s theory is gathering steam. “There’s a caveat to all origins-of-life research, which is that it’s difficult to prove things,” says John Sutherland, a chemist at the Medical Research Council in Cambridge, England. But when a plausible path emerges with many similarities to modern biochemistry, he says, “it’s difficult to escape the conclusion that it is actually the way things happened.”

Sutherland also points out that Szostak’s latest work manages to marry several once-competing origin of life theories. It is based on the so-called “RNA world” hypothesis, which says that RNA is the basis for life’s beginnings. But Szostak borrows protocells from the “lipid world” theory. By including citrate, a product of one of life’s oldest metabolic processes, Sutherland explains, Szostak has now incorporated the “metabolism first” point of view as well. “The time is ripe now to bring together the various strands” of origin-of-life theories, Sutherland says, and peptides — one of which may replace citrate as Szostak refines his research — are the last major outstanding strand.

Editor’s Note: This story was updated on December 18, 2013, to provide the correct affiliation for John Sutherland.

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