Tantalizing clues to the chemical origins of life
A synthetic molecule can reshuffle itself to match a DNA template.
Chemists in the United States have made an artificial DNA-like molecule that can change its sequence to bind to a DNA template without the help of enzymes. The findings could shed light on how molecules underpinning life were first able to emerge from a chemical soup.
The vexing question of how strands of DNA or RNA might have first formed has led many chemists to try and recreate the situation in the lab, using synthetic molecules that stack together to form DNA-like strands. Now, Reza Ghadiri at the Scripps Research Institute in La Jolla, California, has taken a different tack — coming up with a molecule that can pair up with different sequences of DNA by rearranging its own sequence.
RNA and DNA both have a backbone made from sugars and phosphorous-containing units called phosphates. Each unit of the DNA or RNA strand also contains one of four bases. The sequence of these bases — adenine, thymine, guanine and cytosine in the case of DNA — forms the genetic code.
Scientists trying to make self-replicating systems have constructed long DNA- and RNA-like molecules from small, information-carrying units that stack together, in the same way that DNA stacks together from nucleotide units in nature. The problem with these is that, once assembled, the sequence of bases cannot usually be changed.
Ghadiri, however, tried a different approach, hoping to find a method of anchoring bases reversibly so that they bind to the backbone but can also come off again.
Ghadiri and his colleagues first made a short preformed backbone, composed of repeating units of two amino acids (dipeptides) including the amino acid cysteine. They were then able to hang bases on it by adding adenine thioesters. These react reversibly with cysteines in the backbone to leave the adenine bases sticking out, forming a molecule called thioester peptide nucleic acid (tPNA).
In DNA, adenine will only pair up with thymine. When they added a short DNA fragment made up of a string of 20 thymine bases into the mix, their tPNA was able to bind to it. If a different DNA fragment containing the non-complementary adenine bases was thrown in instead, the two strands didn't immediately pair up — showing the tPNA would form only complementary base pairs, in a similar way to DNA.
But because of reversible nature of the thioester bond, the bases can come on and off the peptide backbone — meaning that Ghadiri's tPNA can reorganize itself until it is the right sequence for the added DNA template molecule. "Depending on what template you have in solution, the nucleobases self-assemble to form complementary systems," says Ghadiri. "This is the first example of a sequence adaptation by a nucleic acid structure," he adds. The work is published in Science1.
"It's an enormously imaginative base-pairing system that's completely different to anything in biology," says John Sutherland from the University of Manchester, UK. Sutherland and his colleagues recently made a ribonucleotide, an RNA precursor, using only simple molecules. (See 'RNA world easier to make').
"The [tPNA] molecule has potential to bind to any other sequence, because it's reversible," says Sutherland. "It's a really smart thing to do."
The trick now is to find a way to selectively lock the sequences in place once formed, and Ghadiri is working on this. Sutherland is eager to see him succeed: "Then you could separate two strands and have a covalent copy of the first template, which could act for another reversible assembly." This would itself then be locked into shape and so on, he says. "If [Ghadiri] could do this it would be awesome."
Robert Shapiro, a chemist at New York University who studies the molecular origins of life, says that this new system is still a long way from showing that complex molecules such as DNA or RNA could have formed spontaneously from simple chemicals.
"It is possible to speculate that a system of this type arose during the course of evolution — though well after life began — as a precursor to RNA and DNA," he says. "At the time when life first began, however, only crude chemical mixtures would be expected on early Earth. The idea that such mixtures would spontaneously transform themselves into the systems of the type described here, without the aid of chemists and laboratories, is absurd."
Shapiro says, however, that Ghadiri and colleagues' method is an elegant piece of chemistry, and sees its potential especially in the field of synthetic biology. "More needs to be done to show that [Ghadiri's] system can function as a gene. If it can, then it would be a candidate for service as the genetic component in current efforts to construct a cell artificially," he says.
Ghadiri is coy about the implications of his work for the origins of life, and about whether he has recreated a pre-RNA system. "I find it exquisitely tantalizing that you have simple peptides and nucleobases that can get together to form a genetic system that has sequence adaptability," he says. "It is interesting to dream that peptides and nucleic acids were co-evolved."
- Ura, Y., Beierle, J. M., Leman, L. J., Orgel, L. E. & Ghadiri, M. R. Science advance online publication doi:10.1126/science.1174577 (2009).