Scientists show that manmade nucleic acids
can replicate and evolve, ushering in a new era in synthetic biology.
Synthetic
genetic polymers, broadly referred to as XNAs, can replicate and evolve just
like their naturally occurring counterparts, DNA and RNA, according to a new
study published today (April 19) in Science.
The
results of the research have implications not only for the fields of
biotechnology and drug design, but also for research into the origins of
life—on this planet and beyond.
“It’s a
breakthrough,” said Gerald
Joyce of The Scripps Research Institute in La Jolla, California, who
was not involved in the study—“a beautiful paper in the realm of synthetic
biology.”
“It
shows that you don’t have to stick with the ribose and deoxyribose backbones of
RNA and DNA in order to have transmittable, heritable, and evolvable
information,” added Eric
Kool of Stanford University, California, who also did not participate
in the research.
Over
the years, scientists have created a range of XNAs, in which the ribose or
deoxyribose portions of RNA and DNA are replaced with alternative molecules.
For example, threose is used to make TNA, and anhydrohexitol is used to make
HNA. These polymers, which do not exist naturally, are generally studied with
various biotechnological and therapeutic aims in mind.
But
some researchers, like Philipp Holliger of
the MRC Laboratory of Molecular Biology in Cambridge, UK, think XNAs might also
provide insights into the origins of life. They might help to answer questions
such as, “why is life based on DNA and RNA, and, if we ever find life beyond
earth, is it likely to be based on the same molecule or could there be other
possibilities?” Holliger said.
To get
at some of these questions, Holliger and his colleagues had to first create
enzymes that could replicate XNAs, a necessary first step to evolution. They
did this both by randomly mutating and screening existing DNA polymerases for
their ability to read XNA, and by an iterative process of selecting polymerase
variants with capacities for XNA synthesis. In the end, they had several
polymerases that could synthesize six different types of XNA.
To see
whether XNAs could evolve, they generated random HNA sequences, then selected
for those that could bind to two target molecules. After selection, the HNAs
were amplified by the newly designed polymerases and again selected for their
ability to bind the targets. Eight rounds of selection later, the HNA sequences
were no longer random, as those with a particular target-binding motif became
more abundant. Through selection and replication, the HNAs had evolved.
The
finding in itself is not surprising, said Kool. “Chemists have been working for
20 years to find new backbones for DNA and the feeling always was that it would
be interesting and quite possible that some of them might be replicated one
day.” It was, nevertheless, impressive, he added. “The hard part was finding the
enzymes that could do it. So the big leap ahead for this paper was finding
those enzymes.”
The new
polymerases synthesized XNA through rounds of DNA-to-XNA and XNA-to-DNA
synthesis. Generating polymerases that can make XNA direct from XNA will be the
next step, Holliger said, but it will be a lot harder “because both strands
would be foreign to the polymerase.”
Holliger
also explained that there was actually a benefit to having a DNA intermediate.
“It allowed us to access the whole gamut of technologies that are available for
analyzing DNA sequences.” Working with XNAs uniquely, he said, “is like being
thrown back to the way molecular biology was in the early 1970s, in that we
have to develop all our tools afresh.”
Holliger’s
polymerases maybe the first addition to the XNA toolbox but, as more tools are
created the potential for XNA biology will grow, said Jack Szostak of
Harvard Medical School, who was not involved in the study. “In the longer run,
it may be possible to design and build new forms of life that are based on one
or more of these non-natural genetic polymers,” he said. That said, “I think
it’s too early to say whether such novel life-forms would have any practical
applications,” he added.
Regardless
of what the future holds, the new polymerases could have applications right
away. “We hope to be able to evolve XNA aptamers”—molecules that bind specific
targets—“against medically interesting targets,” Holliger said. Scientists are
already creating DNA and RNA aptamers, but their use in the body is severely
hampered by their susceptibility to naturally occurring nucleases that degrade
DNA and RNA. “XNAs are not natural and so are not susceptible to nucleases,”
explained Joyce. “These things are bullet-proof.”
Beyond
the medical applications of the work, Holliger is finally getting some answers
about the basis of life. “The exciting finding of our work is that there really
seems to be many possibilities,” he said. “There isn’t anything Goldilocks
about DNA or RNA.” Does this mean that life elsewhere in the cosmos is more
likely than previously thought? “I would say a cautious yes,” said Holliger.
V.B.
Pinheiro et al., “Synthetic Genetic Polymers Capable of Heredity and
Evolution,” Science, 336: 341-44, 2012.
Ruth
Williams
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