TNA World

A TNA World?

DNA double-helix structure
Figure 1. The double-helix structure of DNA, resembling a spiral staircase. The bases form the steps of the staircase, while the sugar-phosphate backbones form the railing. Credit: Darryl Leja/Access Excellence.

We all know that DNA (Figure 1) makes up the building blocks for life on Earth. But DNA deoxyribonucleic acid is highly complex. It could not have appeared spontaneously; it must have evolved from a simpler form.

Scientists have put forth the theory that RNA ribonucleic acid (Figure 2) was the predecessor to DNA and evolved into that more-complex molecule. But while RNA is slightly simpler than DNA, it too is very complex. So what is the ancestor of RNA? One recent report suggests that it may have been yet another nucleic acid called (L)-a-threofuranosyl oligonucleotides, also known as TNA.

Dr. Albert Eschenmoser and his colleagues at the Scripps Research Institute in La Jolla, California, and the Federal Institute of Technology in Zürich, Switzerland, chemically synthesized TNA in a number of steps. They found that complementary TNA strands can form stable double helices. The TNA strands can also pair up with complementary strands of RNA and DNA. This ability is thought to be one of the requirements of any system that would be considered a possible ancestor of RNA. A second requirement is that it should be a simpler molecule than RNA.

According to Eschenmoser, the synthesis of TNA is part of a comprehensive decade-long project aimed at understanding the origin of RNA. To investigate potential RNA precursors, the scientists have been creating nucleic acids that are structurally similar to RNA. They study the properties of the alternatives, such as TNA, and compare them with corresponding properties of RNA.

TNA seems to be very similar to RNA in some regards, but overall it is a simpler molecule. Part of this simplicity stems from the structure of its sugar-phosphate backbone.

DNA double-helix structure
Figure 2. Like DNA, the single-helix structure of RNA resembles a spiral staircase. Credit: Darryl Leja/Access Excellence.

The sugar-phosphate backbone of DNA provides the structural support for a coded sequence of information-bearing molecules the bases adenine,thymine,cytosine and guanine (A, T, C and G, for short). In RNA, the T is replaced by a U uracil. Keeping the image of the double helix in mind, the bases form the steps of a spiral staircase while the sugar-phosphate backbones form the railing (Figure 1).

The backbone of DNA and RNA is composed of sugar molecules ribose for RNA and deoxyribose for DNA that contain five carbon atoms. In TNA that backbone is composed of sugar molecules threose that contain only four carbon atoms (Figure 3). Under nonbiological conditions, threose forms easily than ribose.

Comparison of backbones of RNA and TNA
Figure 3. The sugar phosphate backbone (the "railing" of the "spiral staircase") consists of a chain of repeating units. Shown above are the backbones of RNA and of TNA. Image credit: Schöning et. al.

"But it is not only the number of the carbon atoms that makes threose an intrinsically simpler molecule than ribose," Eschenmoser says. It is also the fact that, unlike ribose, "the simplest formation of threose requires only a single type of starting material."

TNA does not occur naturally today. Scientists have to create it in the lab in order to study it. Since we can’t go back in time to witness the evolution of nucleic acids, we will never be able to prove whether natural TNA made an appearance on Earth. Indeed, says Eschenmoser, "talking about TNA as a a possible ancestor of RNA is actually premature."

But scientists can examine the basic properties of TNA and determine whether they could have formed in a prebiotic-Earth environment. "The reason for synthesizing and studying it," Eschenmoser explains, is "to screen the structural neighborhood of RNA for potential nucleic-acid alternatives that could also have fulfilled the function of a genetic system."

The fact that TNA is currently synthetic doesn’t exclude the possibility that it could have formed on early Earth. Because the conditions of a primitive Earth were so different little atmospheric oxygen, high ultraviolet radiation, possibly higher temperatures and volcanic activity chemicals may have combined in very different ways than they do in today’s environment.

"Since the direct evidence has disappeared, it will require an inventive chemist to construct a persuasive scenario," says Dr. Leslie Orgel of the Salk Institute for Biological Studies. "The important issue is whether or not it is possible to make TNA using potentially prebiotic chemistry. That remains to be seen."

Backbone units of RNA, TNA, and p-RNA
Figure 4. The repeating units of the backbones of RNA, TNA, and p-RNA. Image credit: Albert Eschenmoser.

Scientists studying the origins of DNA are confronted with a paradox. DNA needs certain proteins to replicate. But in order to make the correct proteins for this function, modern cells need to have DNA. Since DNA and the proteins are dependent on each other, it is hard to see how either of them could have come first. One answer to this riddle is the RNA world theory, which suggests that both DNA and proteins could be descendants of RNA.

But where did RNA come from? To date, no one has been able to form RNA under in the laboratory under conditions that mimic those believed to have existed on primitive Earth. Some scientists also question whether nucleic acids with a backbone of ribose, or any other sugar molecule, would be stable enough to survive the harsh conditions of early Earth.

So it is generally agreed that RNA must have evolved from an earlier form. While TNA is a good candidate, other polymers that exhibit self-replication and base pairing could have evolved into RNA. Pyranosyl RNA (p-RNA) and peptide nucleic acid (PNA) are two of these alternatives.

TNA is "the best bet so far," says Orgel, "but PNA and p-RNA are also possible."

Double helix of p-RNA
Figure 5. Strands of p-RNA can pair up to make a double-helix structure. Image credit: Albert Eschenmoser.

Like TNA, p-RNA differs from RNA and DNA in the type of sugar that makes up its sugar-phosphate backbone. p-RNA can also pair up in double helices (Figure 5). But p-RNA double helices are structurally incompatible with those formed by DNA and RNA. So p-RNA would not have been able to exchange information with RNA, making it an unlikely RNA predecessor.

Another alternative PNA may be a more likely candidate. PNA has the same chemical backbone as proteins and uses the same nucleic acid bases as RNA (A, T, U and C). It can mimic the behavior of DNA and can bind to single-stranded DNA. Recent experiments suggest that components of PNA can be synthesized under prebiotic conditions. Although PNA’s rigid backbone seems to prevent it from carrying out the same catalytic functions as RNA, PNA is still a strong contender as RNA’s ancestor.

"PNA is a major contribution to our present knowledge of nucleic acid chemistry," Eschenmoser says. "Its formation under potentially geochemical conditions should be studied in order to judge whether it could have been a natural RNA precursor."

What Next?

Eschenmoser plans to continue working on TNA, including the investigation of TNA analogs.

"Continuing the Eschenmoser program is obviously important," says Orgel. But, he adds, "the search for completely different kinds of informational molecules, for example peptides that could replicate, is also worth pursuing."