Even those who doubt the RNA World hypothesis may be hard-pressed to argue against it. Consider the predicament faced by a team of scientists at Scripps Research. They suspected that RNA was a poor candidate for life chemistry’s original self-replicating molecule. RNA, they believed, was simply too sticky. That is, they thought that complementary RNA strands in the primordial ooze would have had a hard time separating because strand-separating enzymes would not have existed yet.
And yet these same scientists had found that an organic compound called diamidophosphate (DAP)—a compound that could have been present in the ooze—could have played a crucial role in modifying ribonucleosides and stringing them together into the first RNA strands. This finding didn’t necessarily favor the RNA World hypothesis. In fact, it was, potentially, compatible with the RNA-DNA World hypothesis, which the Scripps Research team found plausible. But the Scripps Research team hadn’t shown that DAP could do for DNA what it did for RNA.
This deficiency, if it may be called that, has been rectified. In the chemistry journal Angewandte Chemie, the Scripps Research scientists reported that DAP, together with 2‐aminoimidazole, can (amido)phosphorylate and oligomerize deoxynucleosides to form DNA, and do so under conditions similar to those of ribonucleosides.
The details appeared in a paper titled “Prebiotic Phosphorylation and Concomitant Oligomerization of Deoxynucleosides to form DNA.” The paper’s authors say that their new finding is the latest in a series of recent discoveries pointing to the possibility that DNA and its close chemical cousin RNA arose together as products of similar chemical reactions, and that the first self-replicating molecules—the first life forms on Earth—were mixes of the two.
“Recent demonstrations of RNA‐DNA chimeras enabling RNA and DNA replication, coupled with prebiotic co‐synthesis of deoxyribo‐ and ribo‐nucleotides, have resurrected the hypothesis of co‐emergence of RNA and DNA,” the article’s authors wrote. “Combined with previous observations of DAP mediated chemistries and the constructive role of RDNA chimeras, the results reported here help set the stage for systematic investigation of a systems chemistry approach of RNA‐DNA coevolution.”
“The pyrimidine 5’‐O‐amidophosphates are formed in good (≈60%) yields,” the authors detailed. “Intriguingly, the presence of pyrimidine nucleos(t)ides increased the yields of purine‐deoxynucleotides (≈20%). Concomitantly, oligomerization (≈18–31%) is observed with predominantly 3′,5′‐phosphodiester DNA linkages, and some (<5%) pyrophosphates.”
Although the new work may lead to new practical applications in chemistry and biology, its main significance is that it addresses the age-old question of how life on Earth first arose. In particular, it paves the way for more extensive studies of how self-replicating DNA-RNA mixes could have evolved and spread on the primordial Earth and ultimately seeded the more mature biology of modern organisms.
“This finding is an important step toward the development of a detailed chemical model of how the first life forms originated on Earth,” said Ramanarayanan Krishnamurthy, PhD, the article’s senior author and an associate professor of chemistry at Scripps Research.
The finding also nudges the field of origin-of-life chemistry away from the hypothesis that has dominated it in recent decades: The RNA World hypothesis posits that the first replicators were RNA-based, and that DNA arose only later as a product of RNA life forms.
A strand of RNA can attract other individual RNA building blocks, which stick to it to form a sort of mirror-image strand—each building block in the new strand binding to its complementary building block on the original, “template” strand. If the new strand can detach from the template strand, and, by the same process, start templating other new strands, then it has achieved the feat of self-replication that underlies life.
But while RNA strands may be good at templating complementary strands, they are not so good at separating from these strands. Modern organisms make enzymes that can force twinned strands of RNA—or DNA—to go their separate ways, thus enabling replication, but it is unclear how this could have been done in a world where enzymes didn’t yet exist.
Krishnamurthy and colleagues have shown in recent studies that “chimeric” molecular strands that are part DNA and part RNA may have been able to get around this problem, because they can template complementary strands in a less-sticky way that permits them to separate relatively easily.
The chemists also have shown in widely cited papers in the past few years that the simple ribonucleoside and deoxynucleoside building blocks, of RNA and DNA respectively, could have arisen under very similar chemical conditions on the early Earth.
This line of thinking is encouraged by the current study, which suggests that primordial DAP could have been as helpful to DNA as it is to RNA.
“We found, to our surprise, that using DAP to react with deoxynucleosides works better when the deoxynucleosides are not all the same but are instead mixes of different DNA ‘letters’ such as A and T, or G and C, like real DNA,” said Eddy Jiménez, PhD, the study’s first author and a postdoctoral research associate in the Krishnamurthy lab.
“Now that we understand better how a primordial chemistry could have made the first RNAs and DNAs, we can start using it on mixes of ribonucleoside and deoxynucleoside building blocks to see what chimeric molecules are formed—and whether they can self-replicate and evolve,” Krishnamurthy asserted.
He added that the work may also have broad practical applications. The artificial synthesis of DNA and RNA—for example in the PCR technique that underlies COVID-19 tests—amounts to a vast global business but depends on enzymes that are relatively fragile and thus have many limitations. Robust, enzyme-free chemical methods for making DNA and RNA may end up being more attractive in many contexts, Krishnamurthy suggested.