Four new DNA letters, the double alphabet of life

The DNA of life on Earth naturally stores its information in only four key chemicals – guanine, cytosine, adenine and thymine, commonly referred to as G, C, A and T., respectively.

Now scientists have doubled this number of building blocks, creating for the first time an eight-letter synthetic genetic language that seems to store and transcribe information like natural DNA.

In a study published on February 22 in Science¹A consortium of researchers led by Steven Benner, founder of the Foundation for Molecular Evolution Applied in Alachua, Fla., suggests that an expanded genetic alphabet could, in theory, also support life.

"It's a real landmark," says Floyd Romesberg, a chemistry biologist at the Scripps Research Institute in La Jolla, California. The study implies that there is nothing particularly "magical" or special about these four chemicals that have evolved on Earth, says Romesberg. "It's a conceptual breakthrough," he adds.

Normally, when a pair of DNA strands twist into a double helix, the chemicals on each strand will couple: A binds to T and C binds to G.

For a long time, scientists have been trying to add more pairs of these chemicals, also called bases, to this genetic code. For example, Benner created the "unnatural" fundamentals in the 1980s. Other groups followed, Romesberg's lab making headlines in 2014 after inserting a non-natural base pair into a living cell.

But the last study is the first to systematically demonstrate that the complementary non-natural bases are recognizable and related to each other and that the double helix that they form holds the structure.

Benner's team, made up of researchers from various American companies and institutions, created the synthetic letters by modifying the molecular structure of the regular bases. The letters of DNA come together because they form hydrogen bonds: each contains hydrogen atoms, which are attracted by nitrogen atoms or d & # 39; oxygen in their partner. Benner explains that it's a bit like Lego bricks that fit together when holes and teeth line up.

By adjusting these holes and paws, the team has developed several new base pairs, including a pair named S and B and another called P and Z.². In the last article, they describe how they combine these four synthetic bases with natural bases. The researchers call the resulting language of eight letters "hachimoji" after the Japanese words for "eight" and "letter". The additional bases each have a shape similar to one of the four natural ones, but show variations in their binding patterns.

The researchers then conducted a series of experiments that showed that their synthetic sequences share essential properties with natural DNA, essential to life.

Data recovery

To function as an information storage system, DNA must follow predictable rules. The team first demonstrated that, in a manner similar to conventional bases, synthetic bases formed pairs formed reliably. They created hundreds of synthetic DNA molecules and found that the letters were predictably linked to their partners.

They then showed that the structure of the double helices remained stable, regardless of the order in which the synthetic bases were found. This is important because, for life to evolve, the DNA sequences must be able to vary without the entire structure collapsing. Using X-ray diffraction, the team showed that three different sequences of synthetic DNA retained the same structure when crystallized.

According to Philipp Holliger, a senior biologist at the MRC Laboratory of Molecular Biology in Cambridge, UK, this is a substantial advance because of other methods of expanding the body. The genetic alphabet is not structurally sound. Instead of chemicals that use hydrogen bonds to form a pair, these other approaches use water-repellent molecules as bases. These can be placed at intervals between natural letters, but the structure of the DNA breaks down if they are placed in a row.

Finally, the team showed that synthetic DNA can be faithfully transcribed into RNA. "The ability to store information is not very interesting for evolution," says Benner. "You must be able to transfer this information into a molecule that does something."

The conversion of DNA into RNA is a key step for the translation of genetic information into proteins, the beasts of life sum. But some RNA sequences, called aptamers, can themselves bind to specific molecules.

Benner's team created a synthetic DNA that encodes a certain aptamer and then confirmed that the transcription had occurred and that the RNA sequence was working properly.

Holliger says that work is an exciting starting point, but there is still a long way to go before reaching a truly synthetic eight-letter genetic system. A key question, for example, will be whether synthetic DNA can be replicated by polymerases, the enzymes responsible for the synthesis of DNA in organisms during cell division. This has been demonstrated for other methods such as that of Romesberg, which uses water repellent bases.

Variety of life

Benner nonetheless says the work shows that life could potentially be backed by DNA bases with structures different from the four we know, which could be relevant in looking for signatures of life elsewhere in the universe.

The addition of letters to the DNA could also have more down-to-earth applications.

With more diversity in genetic building blocks, scientists could potentially create RNA or DNA sequences that can do better than the standard four letters, including functions going beyond genetic storage.

For example, Benner's group had previously shown that DNA strands comprising Z and P better bound cancer cells than sequences comprising only the four conventional bases.³. Benner has also created a company that markets synthetic DNA for medical diagnosis.

Researchers could potentially use their synthetic DNA to create new proteins as well as RNA. The Benner team has also developed other new base pairs, opening the possibility of creating DNA structures containing 10 or even 12 letters. But the fact that researchers have already extended the genetic alphabet to eight is in itself remarkable, says Romesberg. "It already doubles what nature has."