Chemist
Shows How RNA Can Be the Starting Point for Life
By NICHOLAS
WADE
http://www.nytimes.com/2009/05/14/science/14rna.html
May 14,
2009
An English
chemist has found the hidden gateway to the RNA world, the chemical milieu from
which the first forms of life are thought to have emerged on earth some 3.8
billion years ago.
He has
solved a problem that for 20 years has thwarted researchers trying to
understand the origin of life - how the building blocks of RNA, called
nucleotides, could have spontaneously assembled themselves in the conditions of
the primitive earth. The discovery, if correct, should set researchers on
the right track to solving many other mysteries about the origin of life.
It will also mean that for the first time a plausible explanation exists for
how an information-carrying biological molecule could have emerged through
natural processes from chemicals on the primitive earth.
The author,
John D. Sutherland, a chemist at the University of Manchester, likened his work
to a crossword puzzle in which doing the first clues makes the others
easier. "Whether we've done one across is an open question," he
said. "Our worry is that it may not be right."
Other
researchers say they believe he has made a major advance in prebiotic
chemistry, the study of the natural chemical reactions that preceded the first
living cells. "It is precisely because this work opens up so many
new directions for research that it will stand for years as one of the great
advances in prebiotic chemistry," Jack Szostak of the Massachusetts
General Hospital wrote in a commentary in Nature, where the work is being
published on Thursday.
Scientists
have long suspected that the first forms of life carried their biological
information not in DNA but in RNA, its close chemical cousin. Though DNA
is better known because of its storage of genetic information, RNA performs
many of the trickiest operations in living cells. RNA seems to have
delegated the chore of data storage to the chemically more stable DNA eons
ago. If the first forms of life were based on RNA, then the issue is to
explain how the first RNA molecules were formed.
For more
than 20 years researchers have been working on this problem. The building
blocks of RNA, known as nucleotides, each consist of a chemical base, a sugar
molecule called ribose and a phosphate group. Chemists quickly found
plausible natural ways for each of these constituents to form from natural
chemicals. But there was no natural way for them all to join together.
The
spontaneous appearance of such nucleotides on the primitive earth "would
have been a near miracle," two leading researchers, Gerald Joyce and
Leslie Orgel, wrote in 1999. Others were so despairing that they believed
some other molecule must have preceded RNA and started looking for a pre-RNA
world.
The miracle
seems now to have been explained. In the article in Nature, Dr.
Sutherland and his colleagues Matthew W. Powner and BŽatrice Gerland report
that they have taken the same starting chemicals used by others but have caused
them to react in a different order and in different combinations than in
previous experiments. they discovered their recipe, which is far from
intuitive, after 10 years of working through every possible combination of
starting chemicals.
Instead of
making the starting chemicals form a sugar and a base, they mixed them in a
different order, in which the chemicals naturally formed a compound that is
half-sugar and half-base. When another half-sugar and half-base are
added, the RNA nucleotide called ribocytidine phosphate emerges.
A second
nucleotide is created if ultraviolet light is shined on the mixture. Dr.
Sutherland said he had not yet found natural ways to generate the other two
types of nucleotides found in RNA molecules, but synthesis of the first two was
thought to be harder to achieve.
If all four
nucleotides formed naturally, they would zip together easily to form an RNA
molecule with a backbone of alternating sugar and phosphate groups. The
bases attached to the sugar constitute a four-letter alphabet in which
biological information can be represented.
"My
assumption is that we are here on this planet as a fundamental consequence of
organic chemistry," Dr. Sutherland said. "So it must be chemistry
that wants to work."
The
reactions he has described look convincing to most other chemists.
"The chemistry is very robust - all the yields are good and the chemistry
is simple," said Dr. Joyce, an expert on the chemical origin of life at
the Scripps Research Institute in La Jolla, Calif.
In Dr.
Sutherland's reconstruction, phosphate plays a critical role not only as an
ingredient but also as a catalyst and in regulating acidity. Dr. Joyce
said he was so impressed by the role of phosphate that "this makes me
think of myself not as a carbon-based life form but as a phosphate-based life
form."
Dr.
Sutherland's proposal has not convinced everyone. Dr. Robert Shapiro, a
chemist at New York University, said the recipe "definitely does not meet
my criteria for a plausible pathway to the RNA world." He said that
cyano-acetylene, one of Dr. Sutherland's assumed starting materials, is quickly
destroyed by other chemicals and its appearance in pure form on the early earth
"could be considered a fantasy."
Dr.
Sutherland replied that the chemical is consumed fastest in the reaction he proposes,
and that since it has been detected on Titan there is no reason it should not
have been present on the early earth.
If Dr.
Sutherland's proposal is correct it will set conditions that should help solve
the many other problems in reconstructing the origin of life. Darwin, in
a famous letter of 1871 to the botanist Joseph Hooker, surmised that life began
"in some warm little pond, with all sorts of ammonia and phosphoric
salts." But the warm little pond has given way in recent years to
the belief that life began in some exotic environment like the fissures of a
volcano or in the deep sea vents that line the ocean floor.
Dr.
Sutherland's report supports Darwin. His proposed chemical reaction take
place at moderate temperatures, though one goes best at 60 degrees
Celsius. "It's consistent with a warm pond evaporating as the sun
comes out," he said. His scenario would rule out deep sea vents as the
place where life originated because it requires ultraviolet light.
A serious
puzzle about the nature of life is that most of its molecules are right-handed
or left-handed, whereas in nature mixtures of both forms exist. Dr. Joyce
said he had hoped an explanation for the one-handedness of biological molecules
would emerge from prebiotic chemistry, but Dr. Sutherland's reactions do not
supply any such explanation. One is certainly required because of what is
known to chemists as "original syn," referring to a chemical
operation that can affect a molecule's handedness.
Dr.
Sutherland said he was working on this problem and on others, including how to
enclose the primitive RNA molecules in some kind of membrane as the precursor
to the first living cell.
Did life begin with RNA?
RNA world easier to make
Ingenious chemistry shows how nucleotides may
have formed in the primordial soup.
Richard Van Noorden
An elegant experiment has quashed a major
objection to the theory that life on Earth originated with molecules of RNA.
John Sutherland and his colleagues from the
University of Manchester, UK, created a ribonucleotide, a building block of
RNA, from simple chemicals under conditions that might have existed on the
early Earth.
The feat, never performed before, bolsters the
'RNA world' hypothesis, which suggests that life began when RNA, a polymer
related to DNA that can duplicate itself and catalyse reactions, emerged from a
prebiotic soup of chemicals.
"This is extremely strong evidence for the
RNA world. We don't know if these chemical steps reflect what actually
happened, but before this work there were large doubts that it could happen at
all," says Donna Blackmond, a chemist at Imperial College London.
Molecular choreography
An RNA polymer is a string of ribonucleotides,
each made up of three distinct parts: a ribose sugar, a phosphate group and a
base — either cytosine or uracil, known as pyrimidines, or the purines
guanine or adenine. Imagining how such a polymer might have formed
spontaneously, chemists had thought the subunits would probably assemble
themselves first, then join to form a ribonucleotide. But even in the
controlled atmosphere of a laboratory, efforts to connect ribose and base
together have met with frustrating failure.
The Manchester researchers have now managed to
synthesise both pyrimidine ribonucleotides. Their remedy is to avoid producing
separate ribose-sugar and base subunits. Instead, Sutherland's team makes a
molecule whose scaffolding contains a bond that will turn out to be the key
ribose-base connection. Further atoms are then added around this skeleton, which
unfurls to create the ribonucleotide.
ÒWe had a suspicion there was something good out
there, but it took us 12 years to find it.Ó
John Sutherland
University of Manchester
The final connection is to add a phosphate group.
But that phosphate, although only a reactant in the final stages of the
sequence, influences the entire synthesis, Sutherland's team showed. By
buffering acidity and acting as a catalyst, it guides small organic molecules
into making the right connections.
"We had a suspicion there was something good
out there, but it took us 12 years to find it," Sutherland says.
"What we have ended up with is molecular choreography, where the molecules
are unwitting choreographers." Next, he says, he expects to make purine
ribonucleotides using a similar approach.
The start of something special?
Although Sutherland has shown that it is possible
to build one part of RNA from small molecules, objectors to the RNA-world theory
say the RNA molecule as a whole is too complex to be created using early-Earth
geochemistry. "The flaw with this kind of research is not in the
chemistry. The flaw is in the logic — that this experimental control by
researchers in a modern laboratory could have been available on the early
Earth," says Robert Shapiro, a chemist at New York University.
Sutherland points out that the sequence of steps
he uses is consistent with early-Earth scenarios — those involving
methods such as heating molecules in water, evaporating them and irradiating
them with ultraviolet light. And breaking RNA's synthesis down into small,
laboratory-controlled steps is merely a pragmatic starting point, he says,
adding that his team also has results showing that they can string nucleotides
together, once they have formed. "My ultimate goal is to get a living
system (RNA) emerging from a one-pot experiment. We can pull this off. We just
need to know what the constraints on the conditions are first."
Shapiro sides with supporters of another theory
of life's origins – that because RNA is too complex to emerge from small
molecules, simpler metabolic processes, which eventually catalysed the
formation of RNA and DNA, were the first stirrings of life on Earth.
"They're perfectly entitled to disagree with
us. But having got experimental results, we are on the high ground," says
Sutherland.
"Ultimately, the challenge of prebiotic
chemistry is that there is no way of validating historical hypotheses, however
convincing an individual experiment," points out Steven Benner, who
studies origin-of-life chemistry at the Foundation for Applied Molecular
Evolution, a non-profit research centre in Gainesville, Florida.
Sutherland, though, hopes that ingenious organic
chemistry might provide an RNA synthesis so convincing that it effectively
serves as proof. "We might come up with something so coincidental that one
would have to believe it," he says. "That is the goal of my
career."
References
1. Powner, M. W.,
Gerland, B. & Sutherland, J. D. Nature 459, 239-242 2009 | Article |