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Strange Cousins: Molecular Alternatives to DNA, RNA Offer New Insight Into Life’s Origins
ScienceDaily (Apr. 19, 2012)
— Living systems owe their existence to a pair of information-carrying
molecules: DNA and RNA. These fundamental chemical forms possess two
features essential for life: they display heredity -- meaning they can
encode and pass on genetic information, and they can adapt over time,
through processes of Darwinian evolution.
A long-debated question is whether heredity and evolution could be performed by molecules other than DNA and RNA.
John Chaput, a researcher at ASU's Biodesign Institute, who recently published an article in
Nature Chemistry
describing the evolution of threose nucleic acids, joined a
multidisciplinary team of scientists from England, Belgium and Denmark
to extend these properties to other so-called xeno-nucleic acids or
XNAs.
The group demonstrates for the first time that six of these unnatural
nucleic acid polymers are capable of sharing information with DNA. One
of these XNAs, a molecule referred to as anhydrohexitol nucleic acid or
HNA was capable of undergoing directed evolution and folding into
biologically useful forms.
Their results appear in the current issue of
Science.
The work sheds new light on questions concerning the origins of life
and provides a range of practical applications for molecular medicine
that were not previously available.
Nucleic acid aptamers, which have been engineered through in vitro
selection to bind with various molecules, act in a manner similar to
antibodies -- latching onto their targets with high affinity and
specificity. "This could be great for building new types of diagnostics
and new types of biosensors," Chaput says, pointing out that XNAs are
heartier molecules, not recognized by the natural enzymes that tend to
degrade DNA and RNA. New therapeutics may also arise from experimental
Xenobiology.
Both RNA and DNA embed data in their sequences of four nucleotides --
information vital for conferring hereditary traits and for supplying
the coded recipe essential for building proteins from the 20 naturally
occurring amino acids. Exactly how (and when) this system got its start
however, remains one of the most intriguing and hotly contested areas of
biology.
According to one hypothesis, the simpler RNA molecule preceded DNA as
the original informational conduit. The RNA world hypothesis proposes
that the earliest examples of life were based on RNA and simple
proteins. Because of RNA's great versatility -- it is not only capable
of carrying genetic information but also of catalyzing chemical
reactions like an enzyme -- it is believed by many to have supported
pre-cellular life.
Nevertheless, the spontaneous arrival of RNA through a sequence of
purely random mixing events of primitive chemicals was at the very
least, an unlikely occurrence. "This is a big question," Chaput says.
"If the RNA world existed, how did it come into existence? Was it
spontaneously produced, or was it the product of something that was even
simpler than RNA?"
This pre-RNA world hypothesis has been gaining ground, largely
through investigations into XNAs, which provide plausible alternatives
to the current biological regime and could have acted as chemical
stepping-stones to the eventual emergence of life. The current research
strengthens the case that something like this may have taken place.
Threose nucleic acid or TNA for example, is one candidate for this
critical intermediary role. "TNA does some interesting things," Chaput
says, noting the molecule's capacity to bind with RNA through
antiparallel Watson-Crick base pairing. "This property provides a model
for how XNAs could have transferred information from the pre-RNA world
to the RNA world."
Nucleic acid molecules, including DNA and RNA consist of 3 chemical
components: a sugar group, a triphosphate backbone and combinations of
the four nucleic acids. By tinkering with these structural elements,
researchers can engineer XNA molecules with unique properties. However,
in order for any of these exotic molecules to have acted as a precursor
to RNA in the pre-biotic epoch, they would need to have been able to
transfer and recover their information from RNA. To do this, specialized
enzymes, known as polymerases are required.
Nature has made DNA and RNA polymerases, capable of reading,
transcribing and reverse transcribing normal nucleic acid sequences. For
XNA molecules, however; no naturally occurring polymerases exist. So
the group, led by Phil Holliger at the MRC in England, painstakingly
evolved synthetic polymerases that could copy DNA into XNA and other
polymerases that could copy XNA back into DNA. In the end, polymerases
were discovered that transcribe and reverse-transcribe six different
genetic systems: HNA, CeNA, LNA, ANA, FANA and TNA. The experiments
demonstrated that these unnatural DNA sequences could be rendered into
various XNAs when the polymerases were fed the appropriate XNA
substrates.
Using these enzymes as tools for molecular evolution, the team
evolved the first example of an HNA aptamer through iterative rounds of
selection and amplification. Starting from a large pool of DNA
sequences, a synthetic polymerase was used to copy the DNA library into
HNA. The pool of HNA molecules was then incubated with an arbitrary
target. The small fraction of molecules that bound the target were
separated from the unbound pool, reverse transcribed back into DNA with a
second synthetic enzyme and amplified by PCR. After many repeated
rounds, HNAs were generated that bound HIV trans-activating response RNA
(TAR) and hen egg lysosome (HEL), which were used as binding targets.)
"This is a synthetic Darwinian process," Chaput says. "The same thing
happens inside our cells, but this is done in vitro."
The method for producing XNA polymerases draws on the path-breaking
work of Holliger, one of the lead authors of the current study. The
elegant technique uses cell-like synthetic compartments of water/oil
emulsion to conduct directed evolution of enzymes, particularly
polymerases. By isolating self-replication reactions from each other,
the process greatly improves the accuracy and efficiency of polymerase
evolution and replication. "What nobody had really done before," Chaput
says, "is to take those technologies and apply them to unnatural nucleic
acids. "
Chaput also underlines the importance of an international
collaboration for carrying out this type of research, particularly for
the laborious effort of assembling the triphosphate substrates needed
for each of the 6 XNA systems used in the study:
"What happened here is that a community of scientists came together
and organized around this idea that we could find polymerases that could
be used to open up biology to unnatural polymers. It would have been a
tour de force for any lab to try to synthesize all the triphosphates, as
none of these reagents are commercially available."
The study advances the case for a pre-RNA world, while revealing a
new class of XNA aptamers capable of fulfilling myriad useful roles.
Although many questions surrounding the origins of life persist, Chaput
is optimistic that solutions are coming into view: "Further down the
road, through research like this, I think we'll have enough information
to begin to put the pieces of the puzzle together."
The research group consisted of investigators from the Medical
Research Council (MRC) Laboratory of Molecular Biology, Cambridge, led
by Philipp Holliger; the Institute, Katholieke Universiteit Leuven,
Belgium, led by Piet Herdewijn; the Nucleic Acid Center, Department of
Physics and Chemistry, University of Southern Denmark, led by Jesper
Wengel; and the Biodesign Institute at Arizona State University, led by
John Chaput.
In addition to his appointment at the Biodesign Institute, John
Chaput is an associate professor in the Department of Chemistry and
Biochemistry, in the College of Liberal Arts & Sciences.
