Molecular Midwives: Small helper compounds may have spawned early tools of life on Earth

Life on Earth may owe its existence to a versatile little molecule that busied itself assembling the first genetic material some 4 billion years ago. This idea was proposed several years ago, and biochemists have now demonstrated the prowess of such a molecular midwife at assembling DNA in the lab.

DNA, which contains the genetic information for making proteins, consists of two long strands of stacked chemical units—nucleotides—joined like rungs on a ladder.

Special enzymes carry out the assembly and replication of these molecules.

However, before life emerged on Earth, there were no enzymes, says Nicholas Hud of the Georgia Institute of Technology in Atlanta, so scientists have puzzled over how DNA formed its long polymer chains.

In 2000, Hud and a collaborator suggested that something within Earth’s primordial soup must have aided the assembly of early genetic molecules. To test that hypothesis, Hud and his team selected as their midwife a small molecule called proflavine. They knew that it could bind to both DNA and its cousin RNA, which has the structure of a ladder split in half through the rungs.

When the researchers added small amounts of proflavine to a test tube containing snippets made up of a few nucleotides, the nucleotides assembled into DNA at a rate 1,000 times as fast as that in the absence of proflavine. The researchers describe their experiment in the April 2 Angewandte Chemie.

“The midwives act as a platform for assembling the nucleotides,” suggests Hud. Researchers suspect that small molecules like proflavine were widespread on early Earth.

Hud says that he chose to work with proflavine because it has a flat structure that resembles the structure of two nucleotides joined together as they are in DNA’s rungs. Should a couple of free-floating nucleotides bump into such a molecule, they would quickly align with its structure, he explains.

This would prompt the paired nucleotides to stack on top of the midwife in an energetically stable configuration. Paired nucleotides would continue to stack up, interspersed with midwives, and ultimately form a DNA molecule. Eventually, the midwives would slip out of the DNA, says Hud.

For several decades, researchers have tried to assemble DNA and RNA in the lab without the aid of enzymes. Yet none of the methods proved efficient at generating long polymer chains.

The Georgia Tech group is already working toward using proflavine to assemble RNA molecules in the lab. Over the years, many biologists have become convinced that RNA, and not DNA, initiated life on Earth (see “Quite a Switch,” in this week’s issue: Quite a Switch). That’s because RNA can both carry genetic information and behave as an enzyme.

Ronald Breaker of Yale University says the DNA work provides “very good evidence” of the kind of chemistry that was possible on early Earth. Because it’s difficult for chemists to define precisely what happened billions of years ago, they “can only define likely scenarios,” he says.

It may still turn out, however, that some unexpected chemical event was responsible for life. The exact chemistry could have been “one of the most unlikely events in the history of the universe,” Breaker says. But “it just has to happen once.”

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