RNA AND THE ORIGINS OF LIFE
By Sean Henahan, Access Excellence
SANTA CRUZ, CA - Hitherto unrecognized properties of RNA add
further support to the idea that RNA was the central molecule in
the origin of life, report researchers.
RNA is the only known macromolecule that can both encode
genetic information and also act as a biocatalyst. This
observation forms the basis for the 'RNA world' model which
suggests that both the genetic and enzymatic components of early
cells were RNA molecules. However, this model requires that
ribozymes be able to catalyze a variety of chemical reactions-
whereas known natural ribozymes seem relatively limited in the
This led a team of Harvard University scientists to design
an experiment which would search through trillions of bits of RNA
in search of the missing ribozymes. The researchers used a new
method called "in vitro evolution" to screen 500 trillion bits of
The first stage involved searching for RNA capable of
binding to a desired substrate (biotin), but not necessarily
possessing catalytic activity. The researchers then used
repeated rounds of affinity chromatography and amplification to
generate a second pool of RNA which contained the selected
binding domain sequence. The RNA segments isolated by this
process were subjected to another round of in vitro evolution.
Repeated rounds of in vitro transcription produced one RNA
molecule with the desired attributes.
The researchers then sought to amplify and modify that RNA
molecule so it could catalyze the carbon-nitrogen bond with no
help from proteins. They randomly changed some of the RNA's
genetic units, so that each one had a 30 percent chance of being
different from the corresponding genetic unit in the starting
framework. This led to another huge pool of 80 trillion slightly
different RNAs. Next, the researchers explored the abilities of
these mutated RNAs to stick to the non-RNA substance and to
catalyze the carbon-nitrogen alkylation.
Seven more screening steps led to one ribozyme that could
both bind to the non-RNA substrate and catalyze alkylation. Next
the investigators improved the efficiency of this molecule
100-fold by mutating it further and subjecting it to another
round of screens. However, the ribozyme did not perform its
catalyst role with the speed of proteins that typically do the
"The slowness of this ribozyme might reflect the intrinsic
incompetence of RNA to carry out the reactions that proteins do
so well. That may be why the RNA world evolved into a protein
world--proteins outcompeted RNA in these functions. But we don't
know that our ribozyme is the best one possible. We could
optimize it further," commented molecular biologist Charles
Wilson, now at the UC Santa Cruz.
To the researchers' surprise, the structure of their final
ribozyme looks like that of a well-known RNA molecule in the
cells of all living things: the cloverleaf-shaped "transfer RNA."
Wilson now is trying to determine why this shape arose in the
experiment and how it works. "It's striking to me that we started
with an enormous random pool with no bias," he says, "but we
ended up with basically the only RNA whose structure we really
The discovery of this ribozyme reveals a far broader set of
chemical skills than scientists previously had credited to RNA,
"All other known ribozymes carry out the same basic
reaction: breaking and making bonds in the RNA backbone between
phosphorus and oxygen. Some RNAs cut and paste themselves
together, but that involves similar reactions. To test the idea
of an RNA world, we needed to look for other reactions beyond
this backbone chemistry."
The reaction targeted in this research, the carbon-bonding
process called "alkylation," would have been critical to the
success of RNA as life arose. "This basic reaction comes up in
all types of biological situations," Wilson says. "Our results
suggest that RNA could have reacted with other molecules that
didn't look like RNA. That's the first step of evolution toward a
In today's organisms, nearly all chemical reactions are
catalyzed by proteins, powerful enzymes that have evolved to
master a bewildering array of tasks. However, proteins cannot
a cell's genetic information. That deed is the domain of the
nucleic acids: double-stranded DNA and its single-stranded
relative, RNA. Although DNA is more widely known, scientists have
found that RNA is far more complex and versatile.
Modern proteins and nucleic acids need each other to exist
and function. However, it is extremely unlikely that these two
complex types of molecules evolved together on the young earth.
Within the last decade, biologists have turned to RNA as a way
out of this chicken-and-egg paradox. In addition to acting as a
genetic librarian and stenographer, RNA can mimic proteins by
triggering certain reactions. But until now, that class of
reactions had seemed limited.
For more information on this research see Nature, Vol. 374,
4/27/95, Wilson et al.
Transmitted: 95-04-26 17:36:21 EDT
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