Molecular midwives hold clues to the origin of life

Adding a small molecule, dubbed a “molecular midwife,” researchers increased the rate of DNA formation in a chemical reaction 1,000 fold over a similar reaction lacking a midwife. The discovery is an important step in the effort to trace the evolution of life back to the earliest self-replicating molecules. The results are reported in the April 2 edition of the German chemistry journal Angewandte Chemie.

“We are working to uncover how molecules similar to RNA and DNA first appeared on Earth around 4 billion years ago. Our theory is that small, simple molecules acted as templates for the production of the first RNA-like molecules. Many of these small molecules, or molecular midwives, would have worked together to produce RNA by spontaneously mixing and assembling with the chemical building blocks of RNA,” said Nicholas Hud, associate professor of chemistry and biochemistry at the Georgia Institute of Technology.

In contemporary life, RNA is present in all cells and is responsible for transmitting genetic information from DNA to proteins. Many scientists believe that RNA, or something similar to RNA, was the first molecule on Earth to self-replicate and begin the process of evolution that led to more advanced forms of life such as human beings.

Hud first proposed the idea of a molecular midwife in a paper published in the Journal of Theoretical Biology in 2000, along with co-author Frank Anet, professor emeritus at UCLA. The problem they said was this. When you throw all the components needed to make RNA into a soup, the individual components do not spontaneously form RNA. But there may have been other molecules present at the dawn of life that would have increased the chances RNA would form. If this were true, then it would provide a missing link in the evolution of life’s earliest molecules.

Hud and Anet, along with Georgia Tech students Swapan Jain and Christopher Stahle, tested this idea by using the molecule proflavin to aid the chemical synthesis of DNA (DNA is chemically very similar to RNA and its synthetic reagents were more readily adapted for their test reaction). They found that proflavin accelerates by 1,000 times the rate at which two short DNA molecules become connected into a larger DNA molecule.

“At first, we simply wanted to determine if our idea for the role of a molecular midwife in early life was at all feasible. We used proflavin as a test midwife because it is known to bind in between the base pairs of RNA and DNA, a feature that we believed to be important for midwife activity. Now we are testing other molecules for midwife activity, and attempting to determine which ones could have been present on Earth at the time when life began,” said Hud.

Solving the puzzle of how the first RNA molecules formed is crucial for scientists who want to trace the evolution of life to its origins. In today’s world, DNA, RNA and proteins are all involved in replicating each other. Cells use proteins to replicate DNA and RNA; in turn, RNA is needed to make proteins.

In the early 1980s it was discovered that RNA is capable of both carrying the genetic information needed to make a new molecule and catalyzing chemical reactions; the latter task is currently done primarily by proteins in living cells. So if RNA can do both its own job and that of proteins, then proteins didn’t need to be present for the first RNA molecules to form and replicate. Given that DNA requires one more step to make than RNA, many scientists concluded that RNA was the first molecule of life on earth.

So if RNA came first, how did it get here? Hud’s theory is this. Much like a ladder with one side lopped off, RNA is made up of a long chain of sugars and phosphate groups – known as a polymer backbone – forming one side of the ladder and with four different types of molecules – known as bases – forming the rungs. In the beginning, individual bases may have been connected to sugars and phosphate groups to form molecules called nucleotides. It’s well known that left to their own devices, the bases of nucleotides won’t bond with each other with any great frequency, as they do in the well-known double helix of DNA. But if, Hud and company propose, a molecular midwife such as proflavin were present, it would create a platform on which two bases could stack and pair with each other. As pairs of nucleotide bases stack with interspersed midwives, in a Dagwood-style sandwich, the nucleotides can stitch together to form molecules such as RNA or DNA. Once these molecules are long enough, the midwives can float away and the bases would remain paired in a double helix, or separate to promote the formation of more RNA molecules, depending upon solution conditions.

“Most recently we have demonstrated in our laboratory that proflavin can also work as a molecular midwife for RNA formation, as well as DNA,” said Hud. “We are very excited about these results. However, our ultimate goal is to achieve a self-replicating molecular system that is capable of evolving.” That development, he added, is still several years away.